Biochemistry, Genetics and Molecular Biology › Molecular Biology

Mitochondrial Function and Pathology

Works Count: 130092

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Description

This cluster of papers focuses on the dynamics of mitochondria, the production and regulation of reactive oxygen species (ROS), and their implications in various biological processes such as aging, neurodegenerative diseases, and metabolic regulation. The papers cover topics including mitochondrial fusion and fission, oxidative stress, mitochondrial dysfunction, and the role of mitochondria in cell death.

Keywords

Mitochondria; Reactive Oxygen Species; Oxidative Stress; Mitochondrial Dysfunction; Cell Death; Mitochondrial Fusion; Mitochondrial Fission; Aging; Neurodegenerative Diseases; Metabolic Regulation

Effect of Ischemia on Known Substrates and Cofactors of the Glycolytic Pathway in Brain

1964-01-01

Oliver H. Lowry , Janet V. Passonneau , Francis X. Hasselberger +1 more

The rat nervous system

1985-01-01

George Paxinos

Mitochondrial control of cell death

2000-05-01

Guido Kroemer , John C. Reed

The Cerebellum as a Neuronal Machine

1967-01-01

John C. Eccles , Masao Ito , János Szentágothai

Robbins and Cotran Pathologic Basis of Disease

2020-08-13

Syed A. Hoda , Raza S. Hoda

Robbins and Cotran pathologic basis of disease / , Robbins and Cotran pathologic basis of disease / , کتابخانه دیجیتال جندی شاپور اهواز Robbins and Cotran pathologic basis of disease / , Robbins and Cotran pathologic basis of disease / , کتابخانه دیجیتال جندی شاپور اهواز

Pairwise comparisons of mitochondrial DNA sequences in stable and exponentially growing populations.

1991-10-01

Montgomery Slatkin , R R Hudson

We consider the distribution of pairwise sequence differences of mitochondrial DNA or of other nonrecombining portions of the genome in a population that has been of constant size and in … We consider the distribution of pairwise sequence differences of mitochondrial DNA or of other nonrecombining portions of the genome in a population that has been of constant size and in a population that has been growing in size exponentially for a long time. We show that, in a population of constant size, the sample distribution of pairwise differences will typically deviate substantially from the geometric distribution expected, because the history of coalescent events in a single sample of genes imposes a substantial correlation on pairwise differences. Consequently, a goodness-of-fit test of observed pairwise differences to the geometric distribution, which assumes that each pairwise comparison is independent, is not a valid test of the hypothesis that the genes were sampled from a panmictic population of constant size. In an exponentially growing population in which the product of the current population size and the growth rate is substantially larger than one, our analytical and simulation results show that most coalescent events occur relatively early and in a restricted range of times. Hence, the "gene tree" will be nearly a "star phylogeny" and the distribution of pairwise differences will be nearly a Poisson distribution. In that case, it is possible to estimate r, the population growth rate, if the mutation rate, mu, and current population size, N0, are assumed known. The estimate of r is the solution to ri/mu = ln(N0r) - gamma, where i is the average pairwise difference and gamma approximately 0.577 is Euler's constant.

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The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen

1973-07-15

Alberto Boveris , Britton Chance

1. Pigeon heart mitochondria produce H(2)O(2) at a maximal rate of about 20nmol/min per mg of protein. 2. Succinate-glutamate and malate-glutamate are substrates which are able to support maximal H(2)O(2) … 1. Pigeon heart mitochondria produce H(2)O(2) at a maximal rate of about 20nmol/min per mg of protein. 2. Succinate-glutamate and malate-glutamate are substrates which are able to support maximal H(2)O(2) production rates. With malate-glutamate, H(2)O(2) formation is sensitive to rotenone. Endogenous substrate, octanoate, stearoyl-CoA and palmitoyl-carnitine are by far less efficient substrates. 3. Antimycin A exerts a very pronounced effect in enhancing H(2)O(2) production in pigeon heart mitochondria; 0.26nmol of antimycin A/mg of protein and the addition of an uncoupler are required for maximal H(2)O(2) formation. 4. In the presence of endogenous substrate and of antimycin A, ATP decreases and uncoupler restores the rates of H(2)O(2) formation. 5. Reincorporation of ubiquinone-10 and ubiquinone-3 to ubiquinone-depleted pigeon heart mitochondria gives a system in which H(2)O(2) production is linearly related to the incorporated ubiquinone. 6. The generation of H(2)O(2) by pigeon heart mitochondria in the presence of succinate-glutamate and in metabolic state 4 has an optimum pH value of 7.5. In states 1 and 3u, and in the presence of antimycin A and uncoupler, the optimum pH value is shifted towards more alkaline values. 7. With increase of the partial pressure of O(2) to the hyperbaric region the formation of H(2)O(2) is markedly increased in pigeon heart mitochondria and in rat liver mitochondria. With rat liver mitochondria and succinate as substrate in state 4, an increase in the pO(2) up to 1.97MPa (19.5atm) increases H(2)O(2) formation 10-15-fold. Similar pO(2) profiles were observed when rat liver mitochondria were supplemented either with antimycin A or with antimycin A and uncoupler. No saturation of the system with O(2) was observed up to 1.97MPa (19.5atm). By increasing the pO(2) to 1.97MPa (19.5atm), H(2)O(2) formation in pigeon heart mitochondria with succinate as substrate increased fourfold in metabolic state 4, with antimycin A added the increase was threefold and with antimycin A and uncoupler it was 2.5-fold. In the last two saturation of the system with oxygen was observed, with an apparent K(m) of about 71kPa (0.7-0.8atm) and a V(max.) of 12 and 20nmol of H(2)O(2)/min per mg of protein. 8. It is postulated that in addition to the well-known flavin reaction, formation of H(2)O(2) may be due to interaction with an energy-dependent component of the respiratory chain at the cytochrome b level.

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The estimation of phosphorus

1940-06-01

R. J. L. Allen

Research Article| June 01 1940 The estimation of phosphorus Russell James Laurence Allen Russell James Laurence Allen 1 1The Low Temperature Station for Research in Biochemistry and Biophysics, University of … Research Article| June 01 1940 The estimation of phosphorus Russell James Laurence Allen Russell James Laurence Allen 1 1The Low Temperature Station for Research in Biochemistry and Biophysics, University of Cambridge, and Department of Scientific and Industrial Research, Cambridge Search for other works by this author on: This Site PubMed Google Scholar Biochem J (1940) 34 (6): 858–865. https://doi.org/10.1042/bj0340858 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation Russell James Laurence Allen; The estimation of phosphorus. Biochem J 1 June 1940; 34 (6): 858–865. doi: https://doi.org/10.1042/bj0340858 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search This content is only available as a PDF. © 1940 CAMBRIDGE UNIVERSITY PRESS1940 Article PDF first page preview Close Modal You do not currently have access to this content.

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Mitochondrial Membrane Permeabilization in Cell Death

2007-01-01

Guido Kroemer , Lorenzo Galluzzi , Catherine Brenner

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier … Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Dynamics of mitochondrial DNA evolution in animals: amplification and sequencing with conserved primers.

1989-08-01

Thomas D. Kocher , W. Kelley Thomas , Axel Meyer +4 more

With a standard set of primers directed toward conserved regions, we have used the polymerase chain reaction to amplify homologous segments of mtDNA from more than 100 animal species, including … With a standard set of primers directed toward conserved regions, we have used the polymerase chain reaction to amplify homologous segments of mtDNA from more than 100 animal species, including mammals, birds, amphibians, fishes, and some invertebrates. Amplification and direct sequencing were possible using unpurified mtDNA from nanogram samples of fresh specimens and microgram amounts of tissues preserved for months in alcohol or decades in the dry state. The bird and fish sequences evolve with the same strong bias toward transitions that holds for mammals. However, because the light strand of birds is deficient in thymine, thymine to cytosine transitions are less common than in other taxa. Amino acid replacement in a segment of the cytochrome b gene is faster in mammals and birds than in fishes and the pattern of replacements fits the structural hypothesis for cytochrome b. The unexpectedly wide taxonomic utility of these primers offers opportunities for phylogenetic and population research.

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Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked

1997-02-21

Jie Yang , Xuesong Liu , Kapil N. Bhalla +6 more

Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic … Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.

The Pathophysiology of Mitochondrial Cell Death

2004-07-30

Douglas R. Green , Guido Kroemer

In the mitochondrial pathway of apoptosis, caspase activation is closely linked to mitochondrial outer membrane permeabilization (MOMP). Numerous pro-apoptotic signal-transducing molecules and pathological stimuli converge on mitochondria to induce MOMP. … In the mitochondrial pathway of apoptosis, caspase activation is closely linked to mitochondrial outer membrane permeabilization (MOMP). Numerous pro-apoptotic signal-transducing molecules and pathological stimuli converge on mitochondria to induce MOMP. The local regulation and execution of MOMP involve proteins from the Bcl-2 family, mitochondrial lipids, proteins that regulate bioenergetic metabolite flux, and putative components of the permeability transition pore. MOMP is lethal because it results in the release of caspase-activating molecules and caspase-independent death effectors, metabolic failure in the mitochondria, or both. Drugs designed to suppress excessive MOMP may avoid pathological cell death, and the therapeutic induction of MOMP may restore apoptosis in cancer cells in which it is disabled. The general rules governing the pathophysiology of MOMP and controversial issues regarding its regulation are discussed.

Mitochondrial Fission, Fusion, and Stress

2012-08-30

Richard J. Youle , Alexander M. van der Bliek

Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria … Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis during high levels of cellular stress. Disruptions in these processes affect normal development, and they have been implicated in neurodegenerative diseases, such as Parkinson's.

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Physiological Roles of Mitochondrial Reactive Oxygen Species

2012-10-01

Laura A. Sena , Navdeep S. Chandel

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Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy

1988-12-09

Douglas C. Wallace , Gurparkash Singh , Marie T. Lott +5 more

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in … Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

Mitochondria: Dynamic Organelles in Disease, Aging, and Development

2006-06-01

David C. Chan

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Mitochondrial Diseases in Man and Mouse

1999-03-05

Douglas C. Wallace

Over the past 10 years, mitochondrial defects have been implicated in a wide variety of degenerative diseases, aging, and cancer. Studies on patients with these diseases have revealed much about … Over the past 10 years, mitochondrial defects have been implicated in a wide variety of degenerative diseases, aging, and cancer. Studies on patients with these diseases have revealed much about the complexities of mitochondrial genetics, which involves an interplay between mutations in the mitochondrial and nuclear genomes. However, the pathophysiology of mitochondrial diseases has remained perplexing. The essential role of mitochondrial oxidative phosphorylation in cellular energy production, the generation of reactive oxygen species, and the initiation of apoptosis has suggested a number of novel mechanisms for mitochondrial pathology. The importance and interrelationship of these functions are now being studied in mouse models of mitochondrial disease.

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Premature ageing in mice expressing defective mitochondrial DNA polymerase

2004-05-01

Aleksandra Trifunović , Anna Wredenberg , Maria Falkenberg +7 more

A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies

1990-12-01

Yu‐ichi Goto , Ikuya Nonaka , Satoshi Horai

Close Contacts with the Endoplasmic Reticulum as Determinants of Mitochondrial Ca 2+ Responses

1998-06-12

Rosario Rizzuto , Paolo Pinton , Walter Carrington +5 more

The spatial relation between mitochondria and endoplasmic reticulum (ER) in living HeLa cells was analyzed at high resolution in three dimensions with two differently colored, specifically targeted green fluorescent proteins. … The spatial relation between mitochondria and endoplasmic reticulum (ER) in living HeLa cells was analyzed at high resolution in three dimensions with two differently colored, specifically targeted green fluorescent proteins. Numerous close contacts were observed between these organelles, and mitochondria in situ formed a largely interconnected, dynamic network. A Ca 2+ -sensitive photoprotein targeted to the outer face of the inner mitochondrial membrane showed that, upon opening of the inositol 1,4,5-triphosphate (IP 3 )–gated channels of the ER, the mitochondrial surface was exposed to a higher concentration of Ca 2+ than was the bulk cytosol. These results emphasize the importance of cell architecture and the distribution of organelles in regulation of Ca 2+ signaling.

Mitochondrial formation of reactive oxygen species

2003-10-01

Julio F. Turrens

The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction … The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction is achieved. Other redox centres in the electron transport chain, however, may leak electrons to oxygen, partially reducing this molecule to superoxide anion (O2−•). Even though O2−• is not a strong oxidant, it is a precursor of most other reactive oxygen species, and it also becomes involved in the propagation of oxidative chain reactions. Despite the presence of various antioxidant defences, the mitochondrion appears to be the main intracellular source of these oxidants. This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments. We also discuss various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.

Mitochondrial Complex I Deficiency in Parkinson's Disease

1990-03-01

Anthony H.V. Schapira , Jonathan M. Cooper , David T. Dexter +3 more

Abstract: The structure and function of mitochondrial respiratory‐chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and … Abstract: The structure and function of mitochondrial respiratory‐chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH‐ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP.

Expression of c- fos Protein in Brain: Metabolic Mapping at the Cellular Level

1988-06-03

Stephen M. Sagar , Frank R. Sharp , Tom Curran

The proto-oncogene c- fos is expressed in neurons in response to direct stimulation by growth factors and neurotransmitters. In order to determine whether the c- fos protein (Fos) and Fos-related … The proto-oncogene c- fos is expressed in neurons in response to direct stimulation by growth factors and neurotransmitters. In order to determine whether the c- fos protein (Fos) and Fos-related proteins can be induced in response to polysynaptic activation, rat hindlimb motor/sensory cortex was stimulated electrically and Fos expression examined immunohistochemically. Three hours after the onset of stimulation, focal nuclear Fos staining was seen in motor and sensory thalamus, pontine nuclei, globus pallidus, and cerebellum. Moreover, 24-hour water deprivation resulted in Fos expression in paraventricular and supraoptic nuclei. Fos immunohistochemistry therefore provides a cellular method to label polysynaptically activated neurons and thereby map functional pathways.

The mitochondrial permeability transition

1995-07-01

Mario Zoratti , Ildikò Szabó

The Fine Structure of the Nervous System.

1970-06-01

Virginia M. Tennyson

This is the first atlas of the ultrastructure of the mature nervous system and it is a relatively complete collection of elegant micrographs with an accompanying text. The differing quantity … This is the first atlas of the ultrastructure of the mature nervous system and it is a relatively complete collection of elegant micrographs with an accompanying text. The differing quantity and distribution of perikaryal organelles are compared in pyramidal, Purkinje, and granule cells, neurons from the dorsal root ganglion, and in anterior horn cells. Criteria are listed for the identification of dendrites and axons, as well as for the special characteristics of the axon hillock and node of Ranvier. Considerable space has been given to the illustration of the different types of synapses, especially to their presynaptic and postsynaptic organelles and synaptolemmal membranes. Evidence relating synaptic vesicles to transmitter substances and their possible function is discussed. Protoplasmic and fibrous astrocytes are demonstrated and their possible functions pointed out. Of particular interest is the role that thin astrocytic processes may play in isolating receptive surfaces, thereby preventing axon terminals from influencing

Calcium, ATP, and ROS: a mitochondrial love-hate triangle

2004-09-08

Paul S. Brookes , Yisang Yoon , James L. Robotham +2 more

The mitochondrion is at the core of cellular energy metabolism, being the site of most ATP generation. Calcium is a key regulator of mitochondrial function and acts at several levels … The mitochondrion is at the core of cellular energy metabolism, being the site of most ATP generation. Calcium is a key regulator of mitochondrial function and acts at several levels within the organelle to stimulate ATP synthesis. However, the dysregulation of mitochondrial Ca(2+) homeostasis is now recognized to play a key role in several pathologies. For example, mitochondrial matrix Ca(2+) overload can lead to enhanced generation of reactive oxygen species, triggering of the permeability transition pore, and cytochrome c release, leading to apoptosis. Despite progress regarding the independent roles of both Ca(2+) and mitochondrial dysfunction in disease, the molecular mechanisms by which Ca(2+) can elicit mitochondrial dysfunction remain elusive. This review highlights the delicate balance between the positive and negative effects of Ca(2+) and the signaling events that perturb this balance. Overall, a "two-hit" hypothesis is developed, in which Ca(2+) plus another pathological stimulus can bring about mitochondrial dysfunction.

The Biologic Clock: The Mitochondria?

1972-04-01

Denham Harman

ABSTRACT: The author suggests that the maximal life span of a given mammalian species is largely an expression of genetic control over the rate of oxygen utilization. The latter determines … ABSTRACT: The author suggests that the maximal life span of a given mammalian species is largely an expression of genetic control over the rate of oxygen utilization. The latter determines the rate of accumulation of mitochondrial damage produced by free radical reactions, the rate increasing with the rate of oxygen consumption, which ultimately causes death.

Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development

2003-01-13

Hsiuchen Chen , Scott A. Detmer , Andrew J. Ewald +3 more

Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been … Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or Mfn2 die in midgestation. However, whereas Mfn2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or Mfn2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and Mfn2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.

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Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release

2014-07-01

Dmitry B. Zorov , Magdalena Juhaszova , Steven J. Sollott

Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca 2+ , etc., which must be normalized. Evidence suggests that … Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca 2+ , etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca 2+ ). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form

1991-12-01

Hermann Schägger , Gebhard von Jagow

Oxidative damage and mitochondrial decay in aging.

1994-11-08

Mark K. Shigenaga , Tory M. Hagen , B N Ames

We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions … We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Several mitochondrial functions decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function, in part by increasing cellular ATP production. Such evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.

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A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology

2008-07-01

David J. Pagliarini , Sarah E. Calvo , Betty Chang +7 more

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A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

2005-07-19

Douglas C. Wallace

Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation … Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the age-related diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.

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Mitochondria, Oxidants, and Aging

2005-02-01

Robert S. Balaban , Shino Nemoto , Toren Finkel

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Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

2014-11-04

Edward T. Chouchani , Victoria R. Pell , Edoardo Gaude +7 more

How mitochondria produce reactive oxygen species

2008-12-12

Michael P. Murphy

The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to … The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The flux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2•− production is far lower. The generation of O2•− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2•− generation by mitochondria in vivo from O2•−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.

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Mitochondria: In Sickness and in Health

2012-03-01

Jodi Nunnari , Anu Suomalainen

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Hydroperoxide metabolism in mammalian organs.

1979-07-01

B Chance , Helmut Sies , A Boveris

Fission and selective fusion govern mitochondrial segregation and elimination by autophagy

2008-01-17

Gilad Twig , Álvaro A. Elorza , Anthony Molina +7 more

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Assessing mitochondrial dysfunction in cells

2011-03-29

Martin D. Brand , David G. Nicholls

Assessing mitochondrial dysfunction requires definition of the dysfunction to be investigated. Usually, it is the ability of the mitochondria to make ATP appropriately in response to energy demands. Where other … Assessing mitochondrial dysfunction requires definition of the dysfunction to be investigated. Usually, it is the ability of the mitochondria to make ATP appropriately in response to energy demands. Where other functions are of interest, tailored solutions are required. Dysfunction can be assessed in isolated mitochondria, in cells or in vivo, with different balances between precise experimental control and physiological relevance. There are many methods to measure mitochondrial function and dysfunction in these systems. Generally, measurements of fluxes give more information about the ability to make ATP than do measurements of intermediates and potentials. For isolated mitochondria, the best assay is mitochondrial respiratory control: the increase in respiration rate in response to ADP. For intact cells, the best assay is the equivalent measurement of cell respiratory control, which reports the rate of ATP production, the proton leak rate, the coupling efficiency, the maximum respiratory rate, the respiratory control ratio and the spare respiratory capacity. Measurements of membrane potential provide useful additional information. Measurement of both respiration and potential during appropriate titrations enables the identification of the primary sites of effectors and the distribution of control, allowing deeper quantitative analyses. Many other measurements in current use can be more problematic, as discussed in the present review.

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Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3

1997-08-01

Hua Zou , William J. Henzel , Xuesong Liu +2 more

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The incomplete natural history of mitochondria

2003-12-11

J. William O. Ballard , Michael C. Whitlock

Mitochondrial DNA (mtDNA) has been used to study molecular ecology and phylogeography for 25 years. Much important information has been gained in this way, but it is time to reflect … Mitochondrial DNA (mtDNA) has been used to study molecular ecology and phylogeography for 25 years. Much important information has been gained in this way, but it is time to reflect on the biology of the mitochondrion itself and consider opportunities for evolutionary studies of the organelle itself and its ecology, biochemistry and physiology. This review has four sections. First, we review aspects of the natural history of mitochondria and their DNA to show that it is a unique molecule with specific characteristics that differ from nuclear DNA. We do not attempt to cover the plethora of differences between mitochondrial and nuclear DNA; rather we spotlight differences that can cause significant bias when inferring demographic properties of populations and/or the evolutionary history of species. We focus on recombination, effective population size and mutation rate. Second, we explore some of the difficulties in interpreting phylogeographical data from mtDNA data alone and suggest a broader use of multiple nuclear markers. We argue that mtDNA is not a sufficient marker for phylogeographical studies if the focus of the investigation is the species and not the organelle. We focus on the potential bias caused by introgression. Third, we show that it is not safe to assume a priori that mtDNA evolves as a strictly neutral marker because both direct and indirect selection influence mitochondria. We outline some of the statistical tests of neutrality that can, and should, be applied to mtDNA sequence data prior to making any global statements concerning the history of the organism. We conclude with a critical examination of the neglected biology of mitochondria and point out several surprising gaps in the state of our knowledge about this important organelle. Here we limelight mitochondrial ecology, sexually antagonistic selection, life-history evolution including ageing and disease, and the evolution of mitochondrial inheritance.

THE MITOCHONDRIAL DEATH/LIFE REGULATOR IN APOPTOSIS AND NECROSIS

1998-10-01

Guido Kroemer , Bruno Dallaporta , Matthieu Resche‐Rigon

▪ Abstract Both physiological cell death (apoptosis) and, in some cases, accidental cell death (necrosis) involve a two-step process. At a first level, numerous physiological and some pathological stimuli trigger … ▪ Abstract Both physiological cell death (apoptosis) and, in some cases, accidental cell death (necrosis) involve a two-step process. At a first level, numerous physiological and some pathological stimuli trigger an increase in mitochondrial membrane permeability. The mitochondria release apoptogenic factors through the outer membrane and dissipate the electrochemical gradient of the inner membrane. Mitochondrial permeability transition (PT) involves a dynamic multiprotein complex formed in the contact site between the inner and outer mitochondrial membranes. The PT complex can function as a sensor for stress and damage, as well as for certain signals connected to receptors. Inhibition of PT by pharmacological intervention on mitochondrial structures or mitochondrial expression of the apoptosis-inhibitory oncoprotein Bcl-2 prevents cell death, suggesting that PT is a rate-limiting event of the death process. At a second level, the consequences of mitochondrial dysfunction (collapse of the mitochondrial inner transmembrane potential, uncoupling of the respiratory chain, hyperproduction of superoxide anions, disruption of mitochondrial biogenesis, outflow of matrix calcium and glutathione, and release of soluble intermembrane proteins) entails a bioenergetic catastrophe culminating in the disruption of plasma membrane integrity (necrosis) and/or the activation of specific apoptogenic proteases (caspases) by mitochondrial proteins that leak into the cytosol (cytochrome c, apoptosis-inducing factor) with secondary endonuclease activation (apoptosis). The relative rate of these two processes (bioenergetic catastrophe versus protease and endonuclease activation) determines whether a cell will undergo primary necrosis or apoptosis. The acquisition of the biochemical and ultrastructural features of apoptosis critically relies on the liberation of apoptogenic proteases or protease activators from mitochondria. The fact that mitochondrial events control cell death has major implications for the development of cytoprotective and cytotoxic drugs.

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

2006-10-01

Michael T. Lin , M. Flint Beal

Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging

2005-07-14

Gregory C. Kujoth , Asimina Hiona , Thomas D. Pugh +7 more

Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial … Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.

The Rat Brain in Stereotaxic Coordinates

1982-01-01

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Mitofusin 2 tethers endoplasmic reticulum to mitochondria

2008-12-01

Olga Martins de Brito , Luca Scorrano

Mitochondrial TCA cycle metabolites control physiology and disease

2020-01-03

Inmaculada Martínez‐Reyes , Navdeep S. Chandel

Abstract Mitochondria are signaling organelles that regulate a wide variety of cellular functions and can dictate cell fate. Multiple mechanisms contribute to communicate mitochondrial fitness to the rest of the … Abstract Mitochondria are signaling organelles that regulate a wide variety of cellular functions and can dictate cell fate. Multiple mechanisms contribute to communicate mitochondrial fitness to the rest of the cell. Recent evidence confers a new role for TCA cycle intermediates, generally thought to be important for biosynthetic purposes, as signaling molecules with functions controlling chromatin modifications, DNA methylation, the hypoxic response, and immunity. This review summarizes the mechanisms by which the abundance of different TCA cycle metabolites controls cellular function and fate in different contexts. We will focus on how these metabolites mediated signaling can affect physiology and disease.

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Mitochondrial formation of reactive oxygen species

2003-08-26

Julio F. Turrens

The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction … The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction is achieved. Other redox centres in the electron transport chain, however, may leak electrons to oxygen, partially reducing this molecule to superoxide anion (O2-*). Even though O2-* is not a strong oxidant, it is a precursor of most other reactive oxygen species, and it also becomes involved in the propagation of oxidative chain reactions. Despite the presence of various antioxidant defences, the mitochondrion appears to be the main intracellular source of these oxidants. This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments. We also discuss various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.

Investigating the cardiorespiratory fitness gene COX7A2L in cardiomyocytes: Viability and mitochondrial function

2025-06-25

Ada Nilsen Nordeidet , Gurdeep Marwarha , Øystein Røsand +5 more | PLoS ONE

Low cardiorespiratory fitness (CRF) is a well-established risk factor for cardiovascular disease (CVD) and all-cause mortality. Since CRF is largely genetically determined, understanding the genetic influences on CRF might reveal … Low cardiorespiratory fitness (CRF) is a well-established risk factor for cardiovascular disease (CVD) and all-cause mortality. Since CRF is largely genetically determined, understanding the genetic influences on CRF might reveal the protective mechanisms of high CRF. One gene found to be associated with CRF is COX7A2L . COX7A2L is a mitochondrial supercomplex assembly factor, but its role in cellular metabolism remains a topic of discussion. We hypothesized that COX7A2L could play a role in cellular respiration in cardiomyocytes, affecting cardiac function and CRF. To determine the effect of COX7A2L on cardiomyocyte function, we overexpressed and knocked down COX7A2L in human AC16 cardiomyocytes and performed MTT assays and Seahorse XF Cell Mito Stress Tests to assess cell viability and mitochondrial function. For the mitochondrial function measurements, we stimulated the cells with isoproterenol to investigate if the effect of altering COX7A2L levels would be larger under simulated increased energy demand. Overexpression and knockdown were validated using sandwich ELISA. Our findings showed that altering COX7A2L expression in human AC16 cardiomyocytes did not significantly affect cell viability or mitochondrial function. Further research is necessary to determine whether COX7A2L influences cardiomyocyte function and CRF.

Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer's disease and frontotemporal dementia

2025-06-25

Christy Hung , Miriam Llorian , Koustav Pal +4 more | Cell Reports

The mitochondrial methylation potential gates mitoribosome assembly

2025-06-25

Ruth I.C. Glasgow , Vivek Singh , Lucía Peña‐Pérez +7 more | Nature Communications

Hyperoside flavonoids protect against malathion-induced mitochondrial toxicity in the differentiated SH-SY5Y cells

2025-06-25

Ekramy Elmorsy , Huda A. Al Doghaither , Ayat B. Al‐Ghafari +3 more | Naunyn-Schmiedeberg s Archives of Pharmacology

Abstract Malathion (MAL), an organophosphorus pesticide, is known to induce mitochondrial toxicity in neuronal cells, contributing to neurodegenerative processes. This study aims to investigate the protective effects of hyperoside (HYP), … Abstract Malathion (MAL), an organophosphorus pesticide, is known to induce mitochondrial toxicity in neuronal cells, contributing to neurodegenerative processes. This study aims to investigate the protective effects of hyperoside (HYP), a flavonoid, against mitochondrial dysfunction induced by MAL in differentiated SH-SY5Y cells. Differentiated human neuroblastoma cell lines were treated with various concentrations of MAL (0.01 to 100 mM) and HYP (10 to 40 µM). Cell viability was assessed using MTT and BrdU assays, while mitochondrial function was evaluated through ATP production, mitochondrial membrane potential (MMP), oxygen consumption rates (OCR), mitophagy-related proteins (PARKIN and PINK1) evaluation, and expression of key mitochondrial genes (i.e., ND1 /5, Cy.b , CO1 , and ATP 6/8 ). Bioinformatics analyses were also employed to identify the pathways impacted by MAL exposure, which revealed disruptions in immune responses, apoptosis regulation, and mitochondrial function. MAL treatment resulted in significant concentration-dependent cytotoxicity and reduction in cell viability ( p < 0.001). HYP treatment notably increased cell viability to 115.8 ± 3.5% and 130.1 ± 3.1% of the control cells’ viability at 20 and 40 µM concentrations, respectively. The cotreatment with HYP effectively restored mitochondrial function by increasing ATP levels and mitochondrial membrane potential (MMP), while also enhancing oxidative capacity (OCR). Importantly, HYP mitigated MAL-induced oxidative stress and apoptosis, restoring levels of PARKIN and PINK1 proteins, which are crucial for mitophagy. Additionally, HYP significantly enhanced the expression of mitochondrial genes involved in the electron transport chain in MAL-treated cells. These findings indicate that HYP provides significant protective effects against MAL-induced mitochondrial toxicity in differentiated SH-SY5Y cells, suggesting its potential as a therapeutic agent for mitigating pesticide-related neurotoxicity. Further research on HYP may enhance our understanding of its protective mechanisms and therapeutic applications in neurodegenerative diseases.

Leber Hereditary Optic Neuropathy and Epilepsy in a Mexican Patient

2025-06-24

E. Gómez , Daniel San‐Juan , Laura Luna +1 more | Cureus

MitoQ alleviates mitochondria damage in sepsis-acute lung injury in a citrate synthase dependent manner

2025-06-24

Jiaojiao Sun , Sihao Jin , Zhiqiang Wang | Inflammation Research

Rejuvenating the Mitochondrial Permeability Transition

2025-06-24

Federica Boscolo Nata , Ludovica Tommasin , Elena Frigo +1 more | Oxford University Press eBooks

Abstract The mitochondrial Permeability Transition (PT) refers to a Ca²⁺-dependent increase in the permeability of the inner mitochondrial membrane, mediated by a regulated, high-conductance channel known as the PT pore … Abstract The mitochondrial Permeability Transition (PT) refers to a Ca²⁺-dependent increase in the permeability of the inner mitochondrial membrane, mediated by a regulated, high-conductance channel known as the PT pore (PTP). Long-lasting openings of the PTP lead to matrix swelling, rupture of the outer membrane, and release of cytochrome c—events that are well-recognized as contributing to various pathological conditions. In contrast, transient PTP openings are thought to play a role in maintaining Ca²⁺ homeostasis, although definitive evidence remains elusive, partly due to the unresolved and long-debated molecular identity of the PTP. Recent findings suggest adenosine triphosphate (ATP) synthase and the adenine nucleotide translocator (ANT) as primary candidates involved in PTP formation, with the mechanism of channel formation for both currently under investigation. Whether ATP synthase and ANT form separate pores or cooperate in the PT process remains unclear. Interestingly, these proteins are known to assemble into a higher-order complex called the “ATP synthasome,” although its precise function is not yet defined. This chapter reviews recent literature on the structure and function of the PTP and explores the potential role of the ATP synthasome as a critical hub in the regulation of the PT.

Mutation of NDUFAF2 Linked to Mitochondrial Complex I Deficiency

2025-06-24

Anwar R Alhamad , Aziza Mushiba , Huda Alkhawaja +3 more | Cureus

Tric proteins and TOM complex subunits are involved in the import of short DNA fragments into Arabidopsis mitochondria

2025-06-24

T A Tarasenko , K D Elizova , В. И. Тарасенко +2 more | PROTOPLASMA

Mitochondrial‐Cytosolic Cascade Metabolic Regulation System: A Robust Strategy to Disrupt Multipath Energy Replenishment in Cancer Therapy

2025-06-24

Hong Chen , Lei Peng , Tianming Wang +7 more | Advanced Functional Materials

Abstract Manipulating metabolic rewiring in cancer cells has become a central focus in cancer treatment. However, the intricate, yet not fully elucidated, adaptability of cancer metabolism frequently undermines the effectiveness … Abstract Manipulating metabolic rewiring in cancer cells has become a central focus in cancer treatment. However, the intricate, yet not fully elucidated, adaptability of cancer metabolism frequently undermines the effectiveness of such interventions. Here, a novel cascade metabolic regulation system is presented by manipulating the mitochondria‐cytosol metabolic networks to disrupt multipath energy replenishment in cancer. Specifically, multienzymatic Mn‐LDH nanodiscs are synthesized, which not only impair energy metabolism in mitochondria by triggering mitochondrial dysfunction via self‐cascade catalysis, but also show the activity of blocking the compensatory energy metabolism from cellular glycogen. Concurrently, vessel embolization is combined to obstruct the carbon sources essential for both glycolysis in cytosol and the tricarboxylic acid (TCA) cycle in mitochondria, while simultaneously fostering an environment conducive to Mn‐LDH catalysis. This dual‐pronged regulation strategy induced ATP exhaustion and apoptosis in cancer cells, leading to remarkably enhanced antitumor efficacy in orthotopic liver tumor rabbit models compared to a standard clinical embolization formulation for advanced liver tumors. Moreover, comprehensive mechanism studies across cellular and animal models confirmed that this strategy effectively blocked multifaceted metabolic adaptations within the mitochondria and cytosol of cancer cells. Overall, this work offers a promising platform for metabolic intervention and provides important insights into cancer biology and management.

Allogenic mitochondria transfer improves cardiac function in iPS-cell-differentiated cardiomyocytes of a patient with Barth syndrome

2025-06-24

Ye Seul Kim , Sukdong Yoo , Young Mi Jung +5 more | Experimental & Molecular Medicine

Abstract Barth syndrome (BTHS) is an ultrarare, infantile-onset, X-linked recessive mitochondrial disorder that primarily affects males, owing to mutations in TAFAZZIN , which catalyzes the remodeling of cardiolipin, a mitochondrial … Abstract Barth syndrome (BTHS) is an ultrarare, infantile-onset, X-linked recessive mitochondrial disorder that primarily affects males, owing to mutations in TAFAZZIN , which catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mitochondrial transplantation is a novel technique to treat mitochondrial dysfunction by delivering healthy mitochondria to diseased cells or tissues. Here we explored the possibility of using stem-cell-derived cardiomyocytes as a source of mitochondrial transplantation to treat BTHS. We established induced pluripotent stem (iPS) cells from healthy individuals and from patients with BTHS and differentiated them into cardiomyocytes. The iPS-cell-differentiated cardiomyocytes (CMs) derived from patients with BTHS exhibited less expression of cardiomyocytes markers, such as α-SA, cTnT and cTnI, and smaller cell size than normal iPS-cell-derived CMs. Multielectrode array analysis revealed that BTHS CMs exhibited shorter beat period and longer field potential duration than normal CMs. In addition, mitochondrial morphology and function were impaired and mitophagy was decreased in BTHS CMs compared with normal CMs. Transplantation of mitochondria isolated from normal CMs induced mitophagy in BTHS CMs, mitigated mitochondrial dysfunction and promoted mitochondrial biogenesis. Furthermore, mitochondrial transplantation stimulated cardiac maturation and alleviated cardiac arrhythmia of BTHS CMs. These results suggest that normal CMs are useful for allogeneic transplantation in the treatment of mitochondrial diseases, including BTHS.

Harnessing plant thylakoids to restore cellular function in AKI

2025-06-23

Susan J. Allison | Nature Reviews Nephrology

Preclinical models of mitochondrial dysfunction: mtDNA and nuclear-encoded regulators in diverse pathologies

2025-06-23

D.A. Miller , Stephen L. Archer , Kimberly J. Dunham‐Snary | Frontiers in Aging

Mitochondrial-driven diseases encompass a diverse group of single-gene and complex disorders, all linked to mitochondrial dysfunction, with significant impacts on human health. While there are rare mitochondrial diseases in which … Mitochondrial-driven diseases encompass a diverse group of single-gene and complex disorders, all linked to mitochondrial dysfunction, with significant impacts on human health. While there are rare mitochondrial diseases in which the primary defect resides in mutations in mitochondrial DNA, it is increasingly clear that acquired mitochondrial dysfunction, both genetically- and epigenetically-mediated, complicates common complex diseases, including diabetes, cardiovascular disease and ischemia reperfusion injury, cancer, pulmonary hypertension, and neurodegenerative diseases. It is also recognized that mitochondrial abnormalities not only act by altering metabolism but, through effects on mitochondrial dynamics, can regulate numerous cellular processes including intracellular calcium handling, cell proliferation, apoptosis and quality control. This review examines the crucial role of preclinical models in advancing our understanding of mitochondrial genetic contributions to these conditions. It follows the evolution of models of mitochondrial-driven diseases, from earlier in vitro and in vivo systems to the use of more innovative approaches, such as CRISPR-based gene editing and mitochondrial replacement therapies. By assessing both the strengths and limitations of these models, we highlight their contributions to uncovering disease mechanisms, identifying therapeutic targets, and facilitating novel discoveries. Challenges in translating preclinical findings into clinical applications are also addressed, along with strategies to enhance the accuracy and relevance of these models. This review outlines the current state of the field, the future trajectory of mitochondrial disease modeling, and its potential impact on patient care.

In memory of Professor Ivan Haralampiev, DSc

2025-06-23

Petya Karamfilova | Proglas

Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases

2025-06-23

Federica Davì , Antonella Iaconis , Marika Cordaro +2 more | Foods

In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis … In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as “nutraceutical,” “mitochondrial dysfunction,” and “neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability.

Untangling the mitochondrial web: an in-silico analysis of genetic mutations, protein interactions, and tRNA dynamics in oxidative phosphorylation and disc degeneration

2025-06-23

Megan Collins , Brendon Pearce | Journal of Proteins and Proteomics

Abstract Mitochondrial dysfunction and impaired oxidative phosphorylation play a crucial role in the pathogenesis of various non-communicable and degenerative diseases. Research indicates that these abnormalities are contributed to by the … Abstract Mitochondrial dysfunction and impaired oxidative phosphorylation play a crucial role in the pathogenesis of various non-communicable and degenerative diseases. Research indicates that these abnormalities are contributed to by the genetic interindividual variability in system-wide metabolic dysfunction. The objective of this article was, thus, to generate a biochemical pipeline for single-nucleotide polymorphisms (SNVs) associated with general mitochondrial dysfunction for use in studies researching intervertebral disc degeneration. The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) method was used to find articles and to extract SNV information. Proteins were modelled using AlphaFold Colab (Jumper et al., 2021) and tRNA structures were determined using RNAFold (Gruber et al., 2008). Manual tRNA coding domain sequences (CDS) were also generated using the NCBI and Ensembl to determine the proximity of the mutation to the tRNAs anticodon. A total of 56 SNPs were extracted of which mutations located in protein-coding genes were modelled using AlphaFold Colab (Jumper et al., 2021) and mutations located in the exon regions of tRNA genes were modelled using RNAFold (Gruber et al., 2008). Data on structural and spatial changes for proteins were gathered along with structural and thermodynamic changes for tRNA molecules. From the data gathered, it is evident that in-silico investigation of the identified mutations, regarding their effect on proteins and tRNAs, is important for consideration in the potential development of genotyping assays and drug development. This study has shown the development of a biochemical pipeline that will allow for the assessment of mutations in pharmacogenomics studies.

Tiratricol: First Approval

2025-06-23

Yvette N. Lamb | Drugs

Mitochondrial Regulation of CD8⁺ T Cells: Mechanisms and Therapeutic Modulation

2025-06-23

Xu Chen , Pei Lin , Ye Lu +5 more | Advanced Science

Abstract Mitochondria are integral to the regulation of CD8 + T cell function, critically influencing processes such as activation, differentiation, and long‐term persistence during immune responses. Emerging evidence highlights the … Abstract Mitochondria are integral to the regulation of CD8 + T cell function, critically influencing processes such as activation, differentiation, and long‐term persistence during immune responses. Emerging evidence highlights the detrimental impact of mitochondrial dysfunction on CD8 + T cell activity, contributing to immune exhaustion and impairing both antitumor and antiviral immunity. This underscores the importance of understanding and modulating mitochondrial dynamics to optimize T cell‐based immunotherapies. In this review, a comprehensive and in‐depth analysis of the essential mitochondrial processes—including biogenesis, redox homeostasis, and metabolic reprogramming is provided—that govern CD8 + T cell function and are intricately linked to their therapeutic potential. The current strategies aimed at enhancing mitochondrial function in CD8 + T cells are also examined, focusing on both metabolic reprogramming and mitochondrial‐targeted interventions. Despite these promising approaches, several significant challenges remain, such as achieving selective targeting, addressing mitochondrial plasticity, and mitigating off‐target effects. Overcoming these obstacles will be crucial to improving the clinical efficacy and safety of mitochondrial modulation therapies. As the understanding of mitochondrial dynamics within CD8 + T cells continues to evolve, there is growing potential to leverage these insights to improve immune‐based therapies across a range of diseases, including cancer and viral infections.

Feasibility of Xenogeneic Mitochondrial Transplantation in Neuronal Systems: An Exploratory Study

2025-06-23

Eriko Nakamura , Tomoaki Aoki , Cyrus E. Kuschner +6 more | Life

Mitochondrial transplantation (MTx) has emerged as a potential therapeutic approach for diseases associated with mitochondrial dysfunction, yet its scalability and cross-species feasibility remain underexplored. This study aimed to evaluate the … Mitochondrial transplantation (MTx) has emerged as a potential therapeutic approach for diseases associated with mitochondrial dysfunction, yet its scalability and cross-species feasibility remain underexplored. This study aimed to evaluate the dose-dependent uptake and molecular effects of xenogeneic mitochondrial transplantation (xeno-MTx) using rat-derived mitochondria in mouse neuronal systems. HT-22 hippocampal neuronal cells and a murine model of cardiac arrest-induced global cerebral ischemia were used to assess mitochondrial uptake, gene expression, and mitochondrial DNA presence. Donor mitochondria were isolated from rat pectoralis muscle and labeled with MitoTracker dyes. Flow cytometry and confocal microscopy revealed a dose-dependent increase in donor mitochondrial uptake in vitro. Quantitative PCR demonstrated a corresponding increase in rat-specific mitochondrial DNA and upregulation of Mfn2 and Bak1, with no changes in other fusion, fission, or apoptotic genes. Inhibitor studies indicated that mitochondrial internalization may involve actin-dependent macropinocytosis and cholesterol-sensitive endocytic pathways. In vivo, rat mitochondrial DNA was detected in mouse brains post–xeno-MTx, confirming donor mitochondrial delivery to ischemic tissue. These findings support the feasibility of xeno-MTx and its dose-responsive biological effects in neuronal systems while underscoring the need for further research to determine long-term functional outcomes and clinical applicability.

Acute Bilateral Vision Loss in a Young Male: A Case of Leber’s Hereditary Optic Neuropathy

2025-06-23

Zineb Hilali , Oumaima El Korno , Younes Laarif +2 more | Cureus

Clinical Trial Simulation in Geographic Atrophy: Patient, Caregiver, and Trial Site Staff Perspectives

2025-06-23

Ivana Gunderson , Asma Burale , Bill J Best +3 more | Ophthalmology and Therapy

The perspectives of patients with geographic atrophy (GA) should be considered when planning new clinical trials to ensure that real-world patient needs are addressed. The purpose of this study was … The perspectives of patients with geographic atrophy (GA) should be considered when planning new clinical trials to ensure that real-world patient needs are addressed. The purpose of this study was to explore the perspectives of patients, caregivers, and trial site staff on designing and planning a phase 2 clinical trial in GA. This cross-sectional study included patients with GA and their caregivers, trial site staff, and investigators from Germany, the UK, and the USA. Participants were asked to spend 30 min reviewing a simulated trial design communicated as a simple video animation with a voiceover. Subsequently, a 90-min web-assisted telephone interview and survey was conducted to identify problems with the design of the simulated trial and explore potential solutions and improvements. Patients (n = 11), caregivers (n = 11), and site staff (n = 16) completed the survey after reviewing the simulated trial design. Survey responses suggested that study recruitment could be facilitated via widespread advertisement and by including a short washout period, i.e., the time period during which patients receive no medication prior to commencing the study drug to ensure that other treatments do not impact the study results. Survey suggestions for reducing the burden of trial participation included minimizing the number and frequency of trial visits, enabling assessments to be completed at home, and making the schedule of trial visits flexible. Appropriate investment in study center facilities was recommended. In addition, survey respondents proposed that providing transport could be highly beneficial, potentially enabling patients and caregivers to attend trial visits more easily. This study provides valuable information on the viewpoints of patients, caregivers, and trial site staff regarding trial design. Accounting for these perspectives when designing future clinical trials may help ensure successful trial completion and promote positive perceptions of clinical research.

Ancestral sequence reconstruction of the Mic60 Mitofilin domain reveals residues supporting respiration in yeast

2025-06-22

Friederike M. C. Benning , Tristan A. Bell , Tran H. Nguyen +7 more | Protein Science

Abstract In eukaryotes, cellular respiration takes place in the cristae of mitochondria. The mitochondrial inner membrane protein Mic60, a core component of the mitochondrial contact site and cristae organizing system, … Abstract In eukaryotes, cellular respiration takes place in the cristae of mitochondria. The mitochondrial inner membrane protein Mic60, a core component of the mitochondrial contact site and cristae organizing system, is crucial for the organization and stabilization of crista junctions and its associated functions. While the C‐terminal Mitofilin domain of Mic60 is necessary for cellular respiration, the sequence determinants for this function have remained unclear. Here, we used ancestral sequence reconstruction to generate Mitofilin ancestors up to and including the last opisthokont common ancestor (LOCA). We found that yeast‐lineage derived Mitofilin ancestors as far back as the LOCA rescue respiration. By comparing Mitofilin ancestors, we identified four residues sufficient to explain the respiratory difference between yeast‐ and animal‐derived Mitofilin ancestors. Our results provide a foundation for investigating the conservation of Mic60‐mediated cristae junction interactions.

Vulnerability of mitochondrial OXPHOS complexes in the arcuate nucleus of the hypothalamus of Alzheimer's disease

2025-06-22

Jing Tian , Sai Sreeja Meka , Tienju Wang +2 more | Journal of Alzheimer s Disease

Background With increasing recognition of the heterogeneity of the etiopathogenesis of Alzheimer's disease (AD), clinical and basic research has accentuated a contribution of hypothalamic dysfunction to the development of this … Background With increasing recognition of the heterogeneity of the etiopathogenesis of Alzheimer's disease (AD), clinical and basic research has accentuated a contribution of hypothalamic dysfunction to the development of this neurodegenerative disorder. The arcuate nucleus of the hypothalamus (ARH) plays a critical role in maintaining metabolic homeostasis through its regulation of energy storage and expenditure. Although the importance of mitochondrial bioenergetics to the fitness of ARH neurons has been documented, the functional status of mitochondrial oxidative phosphorylation (OXPHOS) complexes in ARH neurons has not been comprehensively investigated in AD-related settings. Objective This study investigated the mitochondrial OXPHOS complex enzyme activity in ARH of AD patients. Methods We examined ARH mitochondrial OXPHOS complexes and AD-related pathological characteristics in AD patients. We also utilized transcriptome-wide association studies (TWAS) bioinformatics method to predict gene expression changes in ARH mitochondrial-related genes within the AD cohort. Results In this study, we identified mitochondrial complex IV dysfunction in tissue homogenate and synaptosomal fractions of postmortem ARH from patients with AD. Further examination determined a reverse correlation between neuronal complex IV dysfunction and ARH amyloid-β 42. Furthermore, through hypothalamus-specific TWAS analysis we identified multiple AD susceptibility genes that encode key proteins for mitochondrial OXPHOS complex assembly and function. Conclusions Our results suggest that ARH neuronal mitochondrial complex IV dysfunction constitutes a phenotypic change in AD that potentially contribute to ARH neuronal stress and dysmetabolism in patients with AD. These findings form a groundwork for future research to understand a hypothalamic mitochondrial pathway of AD pathogenesis.

Evaluating Cell-Free Circulatory Mitochondrial DNA as a Comprehensive Biomarker for Stress: Meta-Analysis of Psychological and Physiological Stress Responses

2025-06-21

Arpan Chattopadhyay , Harshita Tak , Hemanth Naick B | Biomarkers

Mitochondria play a crucial role in cellular processes such as energy metabolism, reactive oxygen species (ROS) generation, and apoptosis. Mitochondrial dysfunction induced by stress has been implicated in various health … Mitochondria play a crucial role in cellular processes such as energy metabolism, reactive oxygen species (ROS) generation, and apoptosis. Mitochondrial dysfunction induced by stress has been implicated in various health conditions. Circulating cell-free mitochondrial DNA (CFC-MT-DNA) has emerged as a potential biomarker reflecting mitochondrial damage under stress. To evaluate the association between CFC-MT-DNA levels and human stress through a systematic review and meta-analysis of case-control studies. A comprehensive literature search was conducted across PubMed, Web of Science, and ScienceDirect databases up to September 2023. Eight eligible studies assessing CFC-MT-DNA levels in stressed versus control individuals were included. Data were analysed using RevMan 5.4 software. The meta-analysis revealed significantly elevated CFC-MT-DNA levels in individuals experiencing stress (P = 0.03), particularly in psychological stress-related conditions such as bipolar disorder and major depressive disorder. However, no significant increase was observed in physiological stress conditions, including diabetes and sports training. High heterogeneity (I2 = 96%) was observed across studies. CFC-MT-DNA shows promise as a non-invasive biomarker for psychological stress. Further longitudinal and mechanistic studies are needed to clarify its role across different types of stress and its potential clinical utility.

Mitochondria‐Homing Drug Mitochonic Acid 5 Improves Barth Syndrome Myopathy in a Human‐Induced Pluripotent Stem Cell Model and Barth Syndrome Drosophila Model

2025-06-21

Yoshiyasu Tongu , Tomoko Kasahara , Tetsuro Matsuhashi +7 more | The FASEB Journal

ABSTRACT Barth syndrome (BTHS) is a rare disease caused by mutations in the tafazzin gene that affects the heart and muscles; however, to date, no clinically effective drugs are available. … ABSTRACT Barth syndrome (BTHS) is a rare disease caused by mutations in the tafazzin gene that affects the heart and muscles; however, to date, no clinically effective drugs are available. In BTHS, mitochondrial function is reduced owing to changes in cardiolipin metabolism. We developed mitochonic acid 5 (MA‐5), a small‐molecule compound that increases ATP levels, improves mitochondrial dynamics, and is effective in treating mitochondrial and muscle diseases. Therefore, this study examined the effectiveness of MA‐5 in treating BTHS. The mitochondrial functions of four isolated BTHS skin fibroblasts were examined. Human BTHS induced pluripotent stem cell (iPSC) were differentiated into myoblasts and cardiolipin metabolism and mitochondrial functions were analyzed. RNA‐seq was performed to clarify the metabolic changes. Using a Drosophila melanogaster model of BTHS, the effects of MA‐5 on motor performance and cardiac phenotype were examined. MA‐5 improved mitochondrial function and reduced cell death due to oxidative stress in skin fibroblasts of patients with BTHS. MA‐5 promoted ATP production and reduced oxidative stress in human BTHS iPS cell‐derived myoblasts. RNA‐seq analysis revealed that MA‐5 alleviated endoplasmic reticulum stress in BTHS cells. Administration of MA‐5 to BTHS Drosophila improved locomotor ability and tachycardia observed in patients with BTHS. Protein interaction analyses suggested colocalization of ATPase and the MA‐5‐binding protein mitofilin. These data suggested that MA‐5 improves BTHS dysfunction and may serve as a novel therapeutic agent for BTHS.

Dysregulated MEG3 in Myotonic Dystrophy 1: nuclear retention, pathological role, and therapeutic correction by antisense conjugates.

2025-06-21

David Seoane-Miraz , Jessica Stoodley , Natalia Galindo-Riera +7 more | bioRxiv (Cold Spring Harbor Laboratory)

MEG3, a long non-coding RNA (lncRNA), has been shown to play a critical role in regulating apoptosis. Its downregulation inhibits apoptosis in cancer cells, whereas its upregulation has been associated … MEG3, a long non-coding RNA (lncRNA), has been shown to play a critical role in regulating apoptosis. Its downregulation inhibits apoptosis in cancer cells, whereas its upregulation has been associated with cell death in both cardiovascular disease and, more recently, Alzheimer ′s Disease. Here we show that MEG3 is upregulated in Myotonic Dystrophy 1 (DM1). Specifically, we show MEG3 upregulation by several-fold in DM1 human muscle cells and in two DM1 mouse models, HSA-LR and LC15. In human DM1 muscle cells we observe nuclear retention of MEG3 and an increase in its transcript diversity. Furthermore, we observe a general trend of nuclear retention in DM1 affecting lncRNAs and microRNAs (miRNAs), in contrast to mRNAs, when compared to healthy cells. This altered nuclear retention may contribute to the pathological effects of non-coding RNA dysregulation in DM1. Importantly, we demonstrate that treatment with antisense conjugates targeting the repeat expansion causing DM1, an approach currently being tested in Clinical Trials, corrects MEG3 levels in HSA-LR mice, without additional therapeutic interventions targeting MEG3.

Seventeen-year follow-up of mitochondrial myopathy and ataxia in a Chinese family: case reports and literature review

2025-06-21

Yue Liu , Li Hu , Xing Wei +4 more | Documenta Ophthalmologica

Antroquinonol mitigates Tau hyperphosphorylation, neuronal damage and cognitive impairments in a chronic cerebral ischemia rat model

2025-06-21

Lingyu Yang , Chiu-Hao Hsu , Ya‐Wen Cheng +7 more | Biomedicine & Pharmacotherapy

MitCOM-based prognostic model identifies GLUD1 as a key suppressor of glioblastoma growth and invasion through regulation of mitochondrial structure and metabolism

2025-06-21

Yang Li , Chaoying Qin , Long Jiang +4 more | Cancer Cell International

Mitochondrial DNA variations and risk of incident gestational diabetes mellitus: a nested case-control study

2025-06-20

Yuqing Liu , Xiao Li , Maoning Zhao +6 more | Acta Diabetologica

Mitochondrial quality control as a therapeutic target in cardiovascular disease: Mechanistic insights and future directions

2025-06-20

Miao Zhang , Tong Zhang , Rongjun Zou +7 more | Journal of Translational Internal Medicine

Abstract Mitochondrial dysfunction is increasingly recognized as a critical driver in the pathogenesis of cardiovascular diseases. Mitochondrial quality control (MQC) is an ensemble of adaptive mechanisms aimed at maintaining mitochondrial … Abstract Mitochondrial dysfunction is increasingly recognized as a critical driver in the pathogenesis of cardiovascular diseases. Mitochondrial quality control (MQC) is an ensemble of adaptive mechanisms aimed at maintaining mitochondrial integrity and functionality and is essential for cardiomyocyte viability and optimal cardiac performance under the stress of cardiovascular pathology. The key MQC components include mitochondrial fission, fusion, mitophagy, and mitochondria-dependent cell death, each contributing uniquely to cellular homeostasis. The dynamic interplay among these processes is intricately linked to pathological phenomena, such as redox imbalance, calcium overload, dysregulated energy metabolism, impaired signal transduction, mitochondrial unfolded protein response, and endoplasmic reticulum stress. Aberrant mitochondrial fission is an early marker of mitochondrial injury and cardiomyocyte apoptosis, whereas reduced mitochondrial fusion is frequently observed in stressed cardiomyocytes and is associated with mitochondrial dysfunction and cardiac impairment. Mitophagy is a protective, selective autophagic degradation process that eliminates structurally compromised mitochondria, preserving mitochondrial network integrity. However, dysregulated mitophagy can exacerbate cellular injury, promoting cell death. Beyond their role as the primary energy source of the cell, mitochondria are also central regulators of cardiomyocyte survival, mediating apoptosis and necroptosis in reperfused myocardium. Consequently, MQC impairment may be a determining factor in cardiomyocyte fate. This review consolidates current insights into the regulatory mechanisms and pathological significance of MQC across diverse cardiovascular conditions, highlighting potential therapeutic avenues for the clinical management of heart diseases.

Silencing ATF3 mediates mitochondrial homeostasis and improves ischemic stroke through regulating the MAPK signaling pathway

2025-06-20

H. Li , Fan Zhang , Cong Zhang +3 more | Frontiers in Molecular Neuroscience

Mitochondrial homeostasis is crucial for preventing and treatment of ischemic stroke. This study aimed to investigate the role of activating transcription factor 3 (ATF3) in ischemic stroke and mitochondrial homeostasis. … Mitochondrial homeostasis is crucial for preventing and treatment of ischemic stroke. This study aimed to investigate the role of activating transcription factor 3 (ATF3) in ischemic stroke and mitochondrial homeostasis. ATF3 was silenced in oxygen glucose deprivation/reperfusion (OGD/R)-treated HT22 cells to evaluate its effects on cell apoptosis and mitochondrial function. The effects of silencing ATF3 on neurological injury, infarction, adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+), mitofusin 1 (MFN1) and MFN2 were evaluated in stroke rats. Transcriptome sequencing and differential expression analysis were conducted to identify differential expressed genes (DEGs) associated with silencing ATF3, followed by functional enrichment analysis. The mitogen activated protein kinase (MAPK) agonist, anisomycin, was used to investigate the regulation of ATF3 in ischemic stroke and mitochondrial homeostasis via the MAPK pathway. Silencing ATF3 increased cell viability and inhibited apoptosis of OGD/R-induced cells. In stroke rats, silencing ATF3 reduced brain water content, decreased neurological injury and alleviated cerebral infarction. Notably, silencing ATF3 significantly inhibited the production of reactive oxygen species (ROS), increased the concentrations of ATP and NAD+, and upregulated the expression of MFN1 and MFN2. Next, 4,517 DGEs associated with silencing ATF3 were mainly enriched in MAPK signaling pathway. Silencing ATF3 downregulated the expression of phosphorylation-extracellular signal-regulated kinase (p-ERK)/ERK in OGD/R cells. Anisomycin notably reversed the effect of silencing ATF3 on ischemic stroke and mitochondrial homeostasis. Silencing ATF3 attenuates ischemic stroke and improves mitochondrial homeostasis via the MAPK signaling pathway, which shares a novel direction for maintaining mitochondrial homeostasis in ischemic stroke.

How Fast Do Mitochondria Work? A Kinetic Study of Oxidative Phosphorylation

2025-06-20

César Pastrana-Pineda , Luis Javier Melgoza-Ramírez , Erandi M. Islas-Flores +7 more | Journal of Chemical Education

Machine learning to predict mitochondrial diseases by phenotypes

2025-06-19

C.C. Kuo , Hui‐An Chen , Rai-Hseng Hsu +7 more | Mitochondrion

Synaptic mitochondria in aging and neurodegenerative diseases: unraveling their functional decline and vulnerability

2025-06-19

Karina A. Cicali , Angie K. Torres , Cheril Tapia‐Rojas | Neural Regeneration Research

Abstract Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. … Abstract Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfunction of mitochondria, particularly those located at synapses. Synaptic mitochondria are specialized organelles that produce the energy required for synaptic transmission but are also important for calcium homeostasis at these sites. In contrast, non-synaptic mitochondria primarily involve cellular metabolism and long-term energy supply. Both pools of mitochondria differ in their form, proteome, functionality, and cellular role. The proper functioning of synaptic mitochondria depends on processes such as mitochondrial dynamics, transport, and quality control. However, synaptic mitochondria are particularly vulnerable to age-associated damage, characterized by oxidative stress, impaired energy production, and calcium dysregulation. These changes compromise synaptic transmission, reducing synaptic activity and cognitive decline during aging. In the context of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s, the decline of synaptic mitochondrial function is even more pronounced. These diseases are marked by pathological protein accumulation, disrupted mitochondrial dynamics, and heightened oxidative stress, accelerating synaptic dysfunction and neuronal loss. Due to their specialized role and location, synaptic mitochondria are among the first organelles to exhibit dysfunction, underscoring their critical role in disease progression. This review delves into the main differences at structural and functional levels between synaptic and nonsynaptic mitochondria, emphasizing the vulnerability of synaptic mitochondria to the aging process and neurodegeneration. These approaches highlight the potential of targeting synaptic mitochondria to mitigate age-associated cognitive impairment and synaptic degeneration. This review emphasizes the distinct vulnerabilities of hippocampal synaptic mitochondria, highlighting their essential role in sustaining brain function throughout life and their promise as therapeutic targets for safeguarding the cognitive capacities of people of advanced age.

Mitochondrial dysfunction in the regulation of aging and aging-related diseases

2025-06-19

Xianhong Zhang , Yue Gao , S. Zhang +7 more | Cell Communication and Signaling

Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, … Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.

Role of mitochondria in physiological activities, diseases, and therapy

2025-06-19

Lilin Wang , Xiaoting Zhou , T LU | Molecular Biomedicine

Abstract Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it … Abstract Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of damaged mitochondria, maintaining quality control. Mitochondrial transport and communication further enhance their role in cellular processes. In addition, mitochondria are susceptible to damage, resulting in dysfunction and disruption of intracellular homeostasis, which is closely associated with the development of numerous diseases. These include mitochondrial diseases, neurodegenerative diseases, cardiovascular diseases (CVDs) and stroke, metabolic disorders such as diabetes mellitus, cancer, infectious diseases, and the aging process. Given the central role of mitochondria in disease pathology, there is a growing need to understand their mechanisms and develop targeted therapies. This review aims to provide a comprehensive overview of mitochondrial structure and functions, with a particular focus on their roles in disease development and the current therapeutic strategies targeting mitochondria. These strategies include mitochondrial-targeted antioxidants, modulation of mitochondrial dynamics and quality control, mitochondrial genome editing and genetic therapy, and mitochondrial transplantation. We also discuss the challenges currently facing mitochondrial research and highlight potential future directions for development. By summarizing the latest advancements and addressing gaps in knowledge, this review seeks to guide future research and clinical efforts in the field of mitochondrial medicine.

Modelling mitochondrial diseases in neurons In Vitro : A systematic review

2025-06-19

Mariana Zarate-Mendez , Nihal Basha , Oliver Podmanicky +3 more | Journal of Neuromuscular Diseases

Mitochondrial diseases, characterized by disruptions in cellular energy production, manifest diverse clinical phenotypes despite a shared molecular aetiology. Of note is the frequent involvement of the brain in these pathologies. … Mitochondrial diseases, characterized by disruptions in cellular energy production, manifest diverse clinical phenotypes despite a shared molecular aetiology. Of note is the frequent involvement of the brain in these pathologies. Given the inherent challenges associated with accessing human tissue and the limitations of mouse models, especially concerning mitochondrial DNA (mtDNA), in vitro modelling is crucial in elucidating brain-related manifestations of mitochondrial diseases. In this review we recapitulate the current available in vitro models used to study neuronal cell types and advance our understanding of mitochondrial brain disease. This inquiry is especially pertinent considering the scarcity of suitable animal models, necessitating reliance on in vitro models to elucidate underlying molecular mechanisms. We found fifty papers modelling neuronal mechanisms of mitochondrial diseases in-vitro. While there was an even split between nuclear and mtDNA mutations, MELAS was the most commonly modelled syndrome. The emerging technologies in the stem cell field have revolutionized our approach to investigate cellular specificity in mitochondrial diseases, and we found a clear shift from neuroblastoma cell lines to iPSC-derived models. Interestingly, most of these studies reported impaired neuronal differentiation in mutant cells independent of the syndrome being modelled. The generation of appropriate in vitro models and subsequent mechanistic insights will be central for the development of novel therapeutic avenues in the mitochondrial field.

Correction: Interneuron migration impairment and brain region-specific DNA damage response following irradiation during early neurogenesis in mice

2025-06-19

Lisa Berden , Nicholas Rajan , André Claude Mbouombouo Mfossa +7 more | Cellular and Molecular Life Sciences

Early-Onset Hearing Loss in Leber’s Hereditary Optic Neuropathy: A Case Report

2025-06-19

Maria Al Bandari , Enas Nasr , Sharon L. Cushing +1 more | Ear Nose & Throat Journal

Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial disorders that is characterized in young adults and teenagers as bilateral, painless, subacute visual failure. Extraocular manifestations include … Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial disorders that is characterized in young adults and teenagers as bilateral, painless, subacute visual failure. Extraocular manifestations include neurological and cardiac features. Sensorineural hearing loss (SNHL) has not been reported as a clinical feature of this disorder. We report a patient diagnosed with LHON having the common m.11778G>A; p. Arg340 pathogenic variant who was also diagnosed with bilateral mild-to-moderate high-frequency SNHL as a neonate through our provincial newborn screening program. Genetic workup, including a next-generation sequencing “Comprehensive Hereditary Hearing Loss Panel” for common and non-syndromic hearing loss and sequencing of the mitochondrial genome, was negative for a second pathogenic variant. The infectious workup was negative. Non-enhanced magnetic resonance imaging of the brain and internal auditory canal was normal. To our knowledge, SNHL has not been reported before as a clinical feature of patients diagnosed with LHON, and hence this rare and unusual presentation merits reporting.

Lactate and lactylation modifications in neurological disorders

2025-06-19

Yu Gu , Keyang Chen , Chunyan Lei +5 more | Neural Regeneration Research

Abstract Research into lactylation modifications across various target organs in both health and disease has gained significant attention. Many essential life processes and the onset of diseases are not only … Abstract Research into lactylation modifications across various target organs in both health and disease has gained significant attention. Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications. Lactate, once considered merely a byproduct of anaerobic metabolism, has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system. Furthermore, recent studies have emphasized the significant role of lactate in numerous neurological diseases, including Alzheimer’s disease, Parkinson’s disease, acute cerebral ischemic stroke, multiple sclerosis, Huntington’s disease, and myasthenia gravis. The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases, aiming to clarify their mechanisms of action and identify potential therapeutic targets. As such, this work provides an overview of the metabolic regulatory roles of lactate in various disorders, emphasizing its involvement in the regulation of brain function. Additionally, the specific mechanisms of brain lactate metabolism are discussed, suggesting the unique roles of lactate in modulating brain function. As a critical aspect of lactate function, lactylation modifications, including both histone and non-histone lactylation, are explored, with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications, such as lactylation writers and erasers. The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized, revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders. Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.

Mitochondrial damage-associated molecular patterns: Neuroimmunomodulators in central nervous system pathophysiology

2025-06-19

Nicole Brooks , Ishvin Riar , Andis Klegeris | Neural Regeneration Research

Abstract Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. It is driven by non-neuronal glial cells, mainly microglia and … Abstract Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. It is driven by non-neuronal glial cells, mainly microglia and astrocytes. Microglia are the resident immune cells of the central nervous system, while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses. Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances; these can be pathology-associated abnormal structures, such as amyloid β proteins, or damage-associated molecular patterns released from injured cells, including their mitochondria. Once in the extracellular space, damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses. This review considers the following mitochondrial damage-associated molecular patterns: heme, cytochrome c, cardiolipin, adenosine triphosphate, mitochondrial DNA, mitochondrial transcription factor A, N-formyl peptides, and the tricarboxylic acid cycle metabolites: succinate, fumarate, and itaconate. We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system. We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate. Our review demonstrates that some mitochondrial damage-associated molecular patterns, such as cytochrome c, adenosine triphosphate, and mitochondrial transcription factor A, have already demonstrated significant effects on the central nervous system. In contrast, others including cardiolipin, mitochondrial DNA, N-formyl peptides, succinate, fumarate, and itaconate, will require additional studies corroborating their roles as damageassociated molecular patterns in the central nervous system. For all of the reviewed mitochondrial damage-associated molecular patterns, there is a shortage of studies using human cells and tissues, which is identified as a significant knowledge gap. We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied. Such studies could identify novel treatment strategies for multiple neurodegenerative diseases, which are characterized by chronic neuroinflammation and currently lack effective therapies.

Neuroglobin: A promising candidate to treat neurological diseases

2025-06-19

Ivan Millan Yañez , Isabel Torres-Cuevas , Marisol Corral‐Debrinski | Neural Regeneration Research

Abstract Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide. Altogether, the burden of … Abstract Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide. Altogether, the burden of neurological disorders has increased considerably over the past 30 years because of population aging. Overall, neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world’s population continues to grow. Autism spectrum disorder, motor neuron disease, encephalopathy, epilepsy, stroke, ataxia, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease represent a non-exhaustive list of neurological illnesses. These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system. Among the common features of neurological handicaps, we find protein aggregation, oxidative stress, neuroinflammation, and mitochondrial impairment in the target tissues, e.g., the brain, cerebellum, and spinal cord. The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis, are responsible for their dependence on functional mitochondria for their integrity. Reactive oxygen species, produced along with the respiration process within mitochondria, can lead to oxidative stress, which compromises neuronal survival. Besides having an essential role in energy production and oxidative stress, mitochondria are indispensable for an array of cellular processes, such as amino acid metabolism, iron-sulfur cluster biosynthesis, calcium homeostasis, intrinsic programmed cell death (apoptosis), and intraorganellar signaling. Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases, therapies that are effective to diminish or halt neuronal dysfunction/death are rare. Given the genetic complexity responsible for neurological disorders, the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life. A promising candidate is the neuroglobin, a globin superfamily member of 151 amino acids, which is found at high levels in the brain, the eye, and the cerebellum. The protein, which localizes to mitochondria, is involved in electron transfer, oxygen storage and defence against oxidative stress; hence, possessing neuroprotective properties. This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions, which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.

Mitochondria-derived vesicles in neurodegeneration

2025-06-19

Emanuele Marzetti , Riccardo Calvani , Hélio José Coelho‐Júnior +1 more | Neural Regeneration Research

Targeting peripheral processes to protect the central nervous system

2025-06-01

Shen Li , Piotr Walczak , Xunming Ji +1 more | Neuroprotection/Neuroprotection (Chichester, England. Print)

Retraction: Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury

2025-06-01

| PubMed

Retraction: Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury

2025-06-01

| PubMed