Редактирование: OPA1

Dynamin-like 120 kDa protein, mitochondrial precursor (EC 3.6.5.5) (Optic atrophy protein 1) [Contains: Dynamin-like 120 kDa protein, form S1] [KIAA0567]

==Publications==

{{medline-entry
|title=[i]Sirt3[/i] Deficiency Shortens Life Span and Impairs Cardiac Mitochondrial Function Rescued by [i]Opa1[/i] Gene Transfer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31269804
|abstract= Sirtuins, a family of NAD -dependent deacetylases, are recognized as nondispensable regulators of aging processes. Sirtuin 3 ([[SIRT3]]) is the main mitochondrial deacetylase that maintains mitochondrial bioenergetics, an essential prerequisite for healthy aging. In this study, using [i]Sirt3[/i] knockout ([i]Sirt3 [/i]) mice, we sought to establish whether [i]Sirt3[/i] deficiency affected life span, an endpoint that has never been tested formally in mammals, and uncover the mechanisms involved in organ damage associated with aging.   [i]Sirt3 [/i] mice experienced a shorter life span than wild-type mice and severe cardiac damage, characterized by hypertrophy and fibrosis, as they aged. No alterations were found in organs other than the heart. [i]Sirt3[/i] deficiency altered cardiac mitochondrial bioenergetics and caused hyperacetylation of optic atrophy 1 ([[OPA1]]), a [[SIRT3]] target. These changes were associated with aberrant alignment of trans-mitochondrial cristae in cardiomyocytes, and cardiac dysfunction. Gene transfer of deacetylated [i]Opa1[/i] restored cristae alignment in [i]Sirt3 [/i] mice, ameliorated cardiac reserve capacity, and protected the heart against hypertrophy and fibrosis. The translational relevance of these findings is in the data showing that [i][[SIRT3]][/i] silencing in human-induced pluripotent stem cell-derived cardiomyocytes led to mitochondrial dysfunction and altered contractile phenotype, both rescued by [i]Opa1[/i] gene transfer.   Our findings indicate that future approaches to heart failure could include [[SIRT3]] as a plausible therapeutic target.   [[SIRT3]] has a major role in regulating mammalian life span. [i]Sirt3[/i] deficiency leads to cardiac abnormalities, due to defective trans-mitochondrial cristae alignment and impaired mitochondrial bioenergetics. Correcting cardiac [[OPA1]] hyperacetylation through gene transfer diminished heart failure in [i]Sirt3 [/i] mice during aging. [i]Antioxid. Redox Signal.[/i] 31, 1255-1271.
|mesh-terms=* Acetylation
* Animals
* GTP Phosphohydrolases
* Longevity
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Mitochondria, Heart
* Sirtuin 3
|keywords=* SIRT3
* gene transfer
* heart failure
* mammalian life span
* mitochondrial bioenergetics
* trans-mitochondrial cristae alignment
|full-text-url=https://sci-hub.do/10.1089/ars.2018.7703
}}
{{medline-entry
|title=Novel role of the [[SIRT4]]-[[OPA1]] axis in mitochondrial quality control.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31225445
|abstract=Mammalian sirtuins are fundamental regulators of a plethora of cellular functions, including gene expression, proliferation, metabolism, and ultimatively cellular aging and organismal life-span. The mitochondrial sirtuin [[SIRT4]] acts as metabolic tumor suppressor and is down-regulated in many cancer types. We showed that [[SIRT4]] expression was up-regulated during replicative senescence and by different anti-proliferative and senescence inducing stressors, including UVB and ionizing radiation, due to inhibition of its negative regulator, microRNA miR-15b. In our recent studies we addressed the molecular consequences of increased [[SIRT4]] expression for mitochondrial function and quality control. We demonstrated that [[SIRT4]] reduces O  consumption and decreases mitochondrial membrane potential in line with an increased generation of mitochondrial reactive oxygen species (mtROS). This led to the accumulation of dysfunctional mitochondria and a more fused mitochondrial network associated with a decreased mitophagic clearance. Mechanistically, our data indicate that [[SIRT4]] promotes mitochondrial fusion in an enzymatically dependent manner through interaction with and stabilization of the dynamin-related GTPase L-[[OPA1]], thereby opposing fission and mitophagy. Our findings provide novel insight in the role of [[SIRT4]] as stress triggered factor that causes mitochondrial dysfunction and impaired mitochondrial quality control through decreased mitophagy, a major hallmark of aging.

|keywords=* OPA1
* SIRT4
* aging
* mitochondrial quality control
* mitophagy
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551841
}}
{{medline-entry
|title=Inhibition of the Fission Machinery Mitigates [[OPA1]] Impairment in Adult Skeletal Muscles.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31208084
|abstract=The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of [[FGF21]]. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates [[FGF21]] induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors.
|mesh-terms=* Aging
* Animals
* Autophagy
* Dynamins
* Endoplasmic Reticulum Stress
* Fibroblast Growth Factors
* GTP Phosphohydrolases
* Mice, Knockout
* Mitochondria
* Mitochondrial Dynamics
* Mitophagy
* Muscle Weakness
* Muscle, Skeletal
* Muscular Atrophy
* Oxidative Stress
* Proteasome Endopeptidase Complex
* Proteolysis
* Ubiquitin
|keywords=* FGF21
* fission
* mitochondrial fusion
* mitophagy
* muscle dystrophy
* muscle wasting
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627087
}}
{{medline-entry
|title=Increased Degradation Rates in the Components of the Mitochondrial Oxidative Phosphorylation Chain in the Cerebellum of Old Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29503614
|abstract=Brain structures differ in the magnitude of age-related neuron loss with the cerebellum being more affected. An underlying cause could be an age-related decline in mitochondrial bioenergetics. Successful aging of mitochondria reflects a balanced turnover of proteins involved in mitochondrial biogenesis and mitophagy. Thus, an imbalance in mitochondrial turnover can contribute to the diminution of cellular function seen during aging. Mitochondrial biogenesis and mitophagy are mediated by a set of proteins including [[MFN1]], [[MFN2]], [[OPA1]], DRP1, [[FIS1]] as well as DMN1l and [[DNM1]], all of which are required for mitochondrial fission. Using N15 labeling, we report that the turnover rates for DMN1l and [[FIS1]] go in opposite directions in the cerebellum of 22-month-old C57BL6j mice as compared to 3-month-old mice. Previous studies have reported decreased turnover rates for the mitochondrial respiratory complexes of aged rodents. In contrast, we found increased turnover rates for mitochondrial proteins of the oxidative phosphorylation chain in the aged mice as compared to young mice. Furthermore, the turnover rate of the components that are most affected by aging -complex III components ([i]ubiquinol cytochrome C oxidoreductase[/i]) and complex IV components ([i]cytochrome C oxidase[/i])- was significantly increased in the senescent cerebellum. However, the turnover rates of proteins involved in mitophagy (i.e., the proteasomal and lysosomal degradation of damaged mitochondria) were not significantly altered with age. Overall, our results suggest that an age-related imbalance in the turnover rates of proteins involved in mitochondrial biogenesis and mitophagy (DMN1l, [[FIS1]]) in conjunction with an age-related imbalance in the turnover rates of proteins of the complexes III and IV of the electron transfer chain, might impair cerebellar mitochondrial bioenergetics in old mice.

|keywords=* aging
* cerebellum
* mice
* mitochondria
* proteins
* turnover
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820363
}}
{{medline-entry
|title=[[SIRT4]] interacts with [[OPA1]] and regulates mitochondrial quality control and mitophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29081403
|abstract=The stress-responsive mitochondrial sirtuin [[SIRT4]] controls cellular energy metabolism in a NAD -dependent manner and is implicated in cellular senescence and aging. Here we reveal a novel function of [[SIRT4]] in mitochondrial morphology/quality control and regulation of mitophagy. We report that moderate overexpression of [[SIRT4]], but not its enzymatically inactive mutant H161Y, sensitized cells to mitochondrial stress. CCCP-triggered dissipation of the mitochondrial membrane potential resulted in increased mitochondrial ROS levels and autophagic flux, but surprisingly led to increased mitochondrial mass and decreased Parkin-regulated mitophagy. The anti-respiratory effect of elevated [[SIRT4]] was accompanied by increased levels of the inner-membrane bound long form of the GTPase [[OPA1]] (L-[[OPA1]]) that promotes mitochondrial fusion and thereby counteracts fission and mitophagy. Consistent with this, upregulation of endogenous [[SIRT4]] expression in fibroblast models of senescence either by transfection with miR-15b inhibitors or by ionizing radiation increased L-[[OPA1]] levels and mitochondrial fusion in a [[SIRT4]]-dependent manner. We further demonstrate that [[SIRT4]] interacts physically with [[OPA1]] in co-immunoprecipitation experiments. Overall, we propose that the [[SIRT4]]-[[OPA1]] axis is causally linked to mitochondrial dysfunction and altered mitochondrial dynamics that translates into aging-associated decreased mitophagy based on an unbalanced mitochondrial fusion/fission cycle.
|mesh-terms=* Aging
* Cells, Cultured
* Cellular Senescence
* GTP Phosphohydrolases
* HEK293 Cells
* Humans
* Mitochondria
* Mitochondrial Proteins
* Mitophagy
* Oxidative Stress
* Reactive Oxygen Species
* Sirtuins
|keywords=* OPA1
* Sirtuin-4/SIRT4
* aging
* fibroblast
* mitochondrial fusion/fission
* mitochondrial quality control
* mitophagy
* reactive oxygen species/ROS
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680561
}}
{{medline-entry
|title=Optic atrophy 1 mediates coenzyme Q-responsive regulation of respiratory complex IV activity in brain mitochondria.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28890359
|abstract=The oxygen consumption rate (OCR) in brain mitochondria is significantly lower in aged mice than in young mice, and the reduced OCR is rescued by administration of water-solubilized CoQ  to aged mice via drinking water. However, the mechanism behind this remains unclear. Here, we show that the activity of respiratory complex IV (CIV) in brain mitochondria declined in aged mice than in young mice, with no significant change in individual respiratory complex levels and their supercomplex assembly. Reduced CIV activity in the aged mice coincided with reduced binding of optic atrophy 1 ([[OPA1]]) to CIV. Both reduced activity and [[OPA1]] binding of CIV were rescued by water-solubilized CoQ  administration to aged mice via drinking water. OCR and the activity and [[OPA1]] binding of CIV in isolated brain mitochondria from aged mice were restored by incubation with CoQ , but not in the presence of 15-deoxy-prostaglandin J , an inhibitor of a GTPase effector domain-containing GTPase such as [[OPA1]] and DRP1. By contrast, the CoQ -responsive restoration of OCR in the isolated mitochondria was not inhibited by Mdivi-1, a selective inhibitor of DRP1. Thus, we propose a novel function of [[OPA1]] in regulating the CIV activity in brain mitochondria in response to CoQ .
|mesh-terms=* Age Factors
* Aging
* Animals
* Brain
* Electron Transport Complex IV
* GTP Phosphohydrolases
* Male
* Mice, Inbred C57BL
* Mitochondria
* Oxygen Consumption
* Protein Binding
* Ubiquinone

|full-text-url=https://sci-hub.do/10.1016/j.exger.2017.09.002
}}
{{medline-entry
|title=Dietary supplementation with acetyl-l-carnitine counteracts age-related alterations of mitochondrial biogenesis, dynamics and antioxidant defenses in brain of old rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28807823
|abstract=We previously reported the ability of dietary supplementation with acetyl-l-carnitine (ALCAR) to prevent age-related decreases of mitochondrial biogenesis in skeletal muscle and liver of old rats. Here, we investigate the effects of ALCAR supplementation in cerebral hemispheres and cerebellum of old rats by analyzing several parameters linked to mitochondrial biogenesis, mitochondrial dynamics and antioxidant defenses. We measured the level of the coactivators [[PGC]]-1α and [[PGC]]-1β and of the factors regulating mitochondrial biogenesis, finding an age-related decrease of [[PGC]]-1β, whereas [[PGC]]-1α level was unvaried. Twenty eight-month old rats supplemented with ALCAR for one and two months showed increased levels of both factors. Accordingly, the expression of the two transcription factors NRF-1 and [[TFAM]] followed the same trend of [[PGC]]-1β. The level of mtDNA, ND1 and the activity of citrate synthase, were decreased with aging and increased following ALCAR treatment. Furthermore, ALCAR counteracted the age-related increase of deleted mtDNA. We also analyzed the content of proteins involved in mitochondrial dynamics (Drp1, Fis1, [[OPA1]] and MNF2) and found an age-dependent increase of [[MFN2]] and of the long form of [[OPA1]]. ALCAR treatment restored the content of the two proteins to the level of the young rats. No changes with aging and ALCAR were observed for Drp1 and Fis1. ALCAR reduced total cellular levels of oxidized PRXs and counteracted the age-related decrease of PRX3 and [[SOD2]]. Overall, our findings indicate a systemic positive effect of ALCAR dietary treatment and a tissue specific regulation of mitochondrial homeostasis in brain of old rats. Moreover, it appears that ALCAR acts as a nutrient since in most cases its effects were almost completely abolished one month after treatment suspension. Dietary supplementation of old rats with this compound seems a valuable approach to prevent age-related mitochondrial dysfunction and might ultimately represent a strategy to delay age-associated negative consequences in mitochondrial homeostasis.
|mesh-terms=* Acetylcarnitine
* Age Factors
* Aging
* Animals
* Antioxidants
* Brain
* DNA, Mitochondrial
* Dietary Supplements
* Male
* Mitochondria
* Mitochondrial Dynamics
* Mitochondrial Proteins
* Mutation
* Organelle Biogenesis
* Oxidative Stress
* Rats, Inbred F344
* Transcription Factors
|keywords=* Acetyl-l-carnitine
* Aging brain
* Mitochondrial biogenesis
* Mitochondrial dynamics
* PGC-1s signalling cascade
|full-text-url=https://sci-hub.do/10.1016/j.exger.2017.08.017
}}
{{medline-entry
|title=Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28758339
|abstract=Replicative and chronological lifespan are two different modes of cellular aging. Chronological lifespan is defined as the duration during which quiescent normal cells retain their capacity to re-enter the proliferative cycle. This study investigated whether changes in metabolism occur during aging of quiescent normal human fibroblasts (NHFs) and the mechanisms that regulate these changes. Bioenergetics measurements were taken in quiescent NHFs from younger (newborn, 3-day, 5-month, and 1-year) and older (58-, 61-, 63-, 68-, and 70-year) healthy donors as well as NHFs from the same individual at different ages (29, 36, and 46 years). Results show significant changes in cellular metabolism during aging of quiescent NHFs: Old NHFs exhibit a significant decrease in glycolytic flux and lactate levels, and increase in oxygen consumption rate (OCR) and ATP levels compared to young NHFs. Results from the Seahorse XF Cell Mito Stress Test show that old NHFs with a lower Bioenergetic Health Index (BHI) are more prone to oxidative stress compared to young NHFs with a higher BHI. The increase in OCR in old NHFs is associated with a shift in mitochondrial dynamics more toward fusion. Genetic knockdown of mitofusin 1 ([[MFN1]]) and optic atrophy 1 ([[OPA1]]) in old NHFs decreased OCR and shifted metabolism more toward glycolysis. Downregulation of [[MFN1]] and [[OPA1]] also suppressed the radiation-induced increase in doubling time of NHFs. In summary, results show that a metabolic shift from glycolysis in young to mitochondrial respiration in old NHFs occurs during chronological lifespan, and [[MFN1]] and [[OPA1]] regulate this process.
|mesh-terms=* Adult
* Aged
* Aging
* Cell Division
* Cell Respiration
* Cells, Cultured
* Fibroblasts
* GTP Phosphohydrolases
* Gene Expression Regulation
* Glycolysis
* Humans
* Infant
* Infant, Newborn
* Middle Aged
* Mitochondria
* Mitochondrial Dynamics
* Mitochondrial Membrane Transport Proteins
* Oxidative Phosphorylation
* Oxygen Consumption
* RNA, Small Interfering
* Signal Transduction
|keywords=* MFN1
* OPA1
* aging
* metabolism
* mitochondria
* respiration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595680
}}
{{medline-entry
|title=Effects of β-hydroxy-β-methylbutyrate on skeletal muscle mitochondrial content and dynamics, and lipids after 10 days of bed rest in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28705993
|abstract=Loss of muscle mass during periods of disuse likely has negative health consequences for older adults. We have previously shown that β-hydroxy-β-methylbutyrate (HMB) supplementation during 10 days of strict bed rest (BR) attenuates the loss of lean mass in older adults. To elucidate potential molecular mechanisms of HMB effects on muscle during BR and resistance training rehabilitation (RT), we examined mediators of skeletal muscle mitochondrial dynamics, autophagy and atrophy, and intramyocellular lipids. Nineteen older adults (60-76 yr) completed 10 days BR followed by 8-wk RT rehabilitation. Subjects were randomized to either HMB (3 g/day HMB; [i]n[/i] = 11) or control (CON; [i]n[/i] = 8) groups. Skeletal muscle cross-sectional area (CSA) was determined by histology from percutaneous vastus lateralis biopsies. We measured protein markers of mitochondrial content [oxidative phosphorylation (OXPHOS)], fusion and fission ([[MFN2]], [[OPA1]], [[FIS1]], and DRP1), autophagy (Beclin1, LC3B, and [[BNIP3]]), and atrophy [poly-ubiquinated proteins (poly-ub)] by Western blot. Fatty acid composition of several lipid classes in skeletal muscle was measured by infusion-MS analysis. Poly-ub proteins and OXPHOS complex I increased in both groups following BR ([i]P[/i] < 0.05, main effect for time), and muscle triglyceride content tended to increase following BR in the HMB group ([i]P[/i] = 0.055). RT rehabilitation increased OXPHOS complex II protein ([i]P[/i] < 0.05), and total OXPHOS content tended ([i]P[/i] = 0.0504) to be higher in HMB group. In addition, higher levels of DRP1 and [[MFN2]] were maintained in the HMB group after RT ([i]P[/i] < 0.05). [[BNIP3]] and poly-ub proteins were significantly reduced following rehabilitation in both groups ([i]P[/i] < 0.05). Collectively, these data suggest that HMB influences mitochondrial dynamics and lipid metabolism during disuse atrophy and rehabilitation.  Mitochondrial content and dynamics remained unchanged over 10 days of BR in older adults. HMB stimulated intramuscular lipid storage as triacylglycerol following 10 days of bed rest (BR) and maintained higher mitochondrial OXPHOS content and dynamics during the 8-wk resistance exercise rehabilitation program.
|mesh-terms=* Age Factors
* Aged
* Autophagy
* Bed Rest
* Double-Blind Method
* Energy Metabolism
* Female
* Humans
* Lipid Metabolism
* Male
* Middle Aged
* Mitochondria, Muscle
* Mitochondrial Dynamics
* Mitochondrial Proteins
* Prospective Studies
* Proteolysis
* Quadriceps Muscle
* Resistance Training
* Sarcopenia
* Signal Transduction
* Time Factors
* Treatment Outcome
* Valerates
|keywords=* HMB
* aging
* bed rest
* exercise
* mitochondria
|full-text-url=https://sci-hub.do/10.1152/japplphysiol.00192.2017
}}
{{medline-entry
|title=Age-Associated Loss of [[OPA1]] in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28552492
|abstract=Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 ([[OPA1]]), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of [[FGF21]] compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging.
|mesh-terms=* Aging
* Animals
* Cellular Senescence
* Endoplasmic Reticulum Stress
* Fibroblast Growth Factors
* GTP Phosphohydrolases
* Inflammation
* Mice
* Muscle, Skeletal
* Muscular Atrophy
* Organ Size
* Unfolded Protein Response
|keywords=* FGF21
* FoxO
* Opa1
* aging
* inflammation
* mitochondria
* muscle
* oxidative stress
* sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462533
}}
{{medline-entry
|title=Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28108329
|abstract=Exercise is known to have numerous beneficial effects. Recent studies indicate that exercise improves mitochondrial energetics not only in skeletal muscle but also in other tissues. While exercise elicits positive effects on memory, neurogenesis, and synaptic plasticity, the effects of exercise on brain mitochondrial energetics remain relatively unknown. Herein, we studied the effects of exercise training in old and young mice on brain mitochondrial energetics, in comparison to known effects on peripheral tissues that utilize fatty acid oxidation. Exercise improved the capacity for muscle and liver to oxidize palmitate in old mice, but not young mice. In the brain, exercise increased rates of respiration and reactive oxygen species (ROS) production in the old group only while utilizing complex I substrates, effects that were not seen in the young group. Coupled complex I to III enzymatic activity was significantly increased in old trained versus untrained mice with no effect on coupled II to III enzymatic activity. Mitochondrial protein content and markers of mitochondrial biogenesis (PGC-1α and TFAM) were not affected by exercise training in the brain, in contrast to the skeletal muscle of old mice. Brain levels of the autophagy marker LC3-II and protein levels of other signaling proteins that regulate metabolism or transport (BDNF, HSP60, phosphorylated mTOR, [[FNDC5]], SIRT3) were not significantly altered. Old exercised mice showed a significant increase in DRP1 protein levels in the brain without changes in phosphorylation, while [[MFN2]] and [[OPA1]] protein levels were unchanged. Our results suggest that exercise training in old mice can improve brain mitochondrial function through effects on electron transport chain function and mitochondrial dynamics without increasing mitochondrial biogenesis.
|mesh-terms=* Aging
* Animals
* Cerebellar Cortex
* Dynamins
* Electron Transport Complex I
* Male
* Mice
* Mice, Inbred C57BL
* Mitochondria, Muscle
* Mitochondrial Dynamics
* Mitochondrial Proteins
* Organelle Biogenesis
* Physical Conditioning, Animal
* Reactive Oxygen Species
* Signal Transduction
|keywords=* Brain
* Complex I
* Cortex
* DRP1
* Exercise
* Mitochondria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346470
}}
{{medline-entry
|title=Physical exercise in aging human skeletal muscle increases mitochondrial calcium uniporter expression levels and affects mitochondria dynamics.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28039397
|abstract=Age-related sarcopenia is characterized by a progressive loss of muscle mass with decline in specific force, having dramatic consequences on mobility and quality of life in seniors. The etiology of sarcopenia is multifactorial and underlying mechanisms are currently not fully elucidated. Physical exercise is known to have beneficial effects on muscle trophism and force production. Alterations of mitochondrial Ca  homeostasis regulated by mitochondrial calcium uniporter ([[MCU]]) have been recently shown to affect muscle trophism in vivo in mice. To understand the relevance of [[MCU]]-dependent mitochondrial Ca  uptake in aging and to investigate the effect of physical exercise on [[MCU]] expression and mitochondria dynamics, we analyzed skeletal muscle biopsies from 70-year-old subjects 9 weeks trained with either neuromuscular electrical stimulation (ES) or leg press. Here, we demonstrate that improved muscle function and structure induced by both trainings are linked to increased protein levels of [[MCU]] Ultrastructural analyses by electron microscopy showed remodeling of mitochondrial apparatus in ES-trained muscles that is consistent with an adaptation to physical exercise, a response likely mediated by an increased expression of mitochondrial fusion protein [[OPA1]]. Altogether these results indicate that the ES-dependent physiological effects on skeletal muscle size and force are associated with changes in mitochondrial-related proteins involved in Ca  homeostasis and mitochondrial shape. These original findings in aging human skeletal muscle confirm the data obtained in mice and propose [[MCU]] and mitochondria-related proteins as potential pharmacological targets to counteract age-related muscle loss.
|mesh-terms=* Aged
* Aging
* Atrophy
* Calcium Channels
* Electric Stimulation
* Exercise
* Female
* Humans
* Insulin-Like Growth Factor I
* Isometric Contraction
* Male
* Mitochondria
* Muscle, Skeletal
* Sarcopenia
* Sedentary Behavior
|keywords=* Aging skeletal muscle
* electrical stimulation
* mitochondria Ca2  uptake
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210373
}}
{{medline-entry
|title=Mitochondrial activity and dynamics changes regarding metabolism in ageing and obesity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27993601
|abstract=Mitochondria play an essential role in ageing and longevity. During ageing, a general deregulation of metabolism occurs, affecting molecular, cellular and physiological activities in the organism. Dysfunction of mitochondria has been associated with ageing and age-related diseases indicating their importance in the maintenance of cell homeostasis. Three major nutritional sensors, mTOR, AMPK and Sirtuins are involved in the control of mitochondrial physiology. These nutritional sensors control mitochondrial biogenesis, dynamics by regulating fusion and fission processes, and turnover through mito- and autophagy. Apart of the known factors involved in fusion, [[OPA1]] and mitofusins, and fission, DRP1 and [[FIS1]], emerging factors such as prohibitins and sestrins can play important functions in mitochondrial dynamics regulation. Mitochondria is also affected by sexual hormones that suffer drastic changes during ageing. The recent literature demonstrates the complex interaction between nutritional sensors and mitochondrial homeostasis in the physiology of adipose tissue and in the accumulation of fat in other organs such as muscle and liver. In this article, the role of mitochondrial homeostasis in ageing and age-dependent fat accumulation is revised. This review highlights the importance of mitochondria in the accumulation of fat during ageing and related diseases such as obesity, metabolic syndrome or type 2 diabetes mellitus.
|mesh-terms=* AMP-Activated Protein Kinases
* Aging
* Animals
* Dynamins
* GTP Phosphohydrolases
* Humans
* Membrane Proteins
* Microtubule-Associated Proteins
* Mitochondria
* Mitochondrial Proteins
* Obesity
* Sirtuins
* TOR Serine-Threonine Kinases
|keywords=* Ageing
* Fat
* Gender
* Inflammation
* Mitochondria
|full-text-url=https://sci-hub.do/10.1016/j.mad.2016.12.005
}}
{{medline-entry
|title='Mitotherapy' for Heart Failure.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26965961
|abstract=Abnormalities in mitochondrial dynamics along with those for the molecular mediators involved are presently being viewed with increased interest in the field of cardiovascular disease. Recent research highlights [[OPA1]], a dynamin-like GTPase mediating mitochondrial fusion, as well as the 'mitoproteases' [[OMA1]] and YME1L, as potential therapeutic targets against heart failure. 
|mesh-terms=* Animals
* Female
* Heart Failure
* Male
* Mitochondria, Heart
* Mitochondrial Dynamics
* Mitophagy
* Myocardium
|keywords=* aging
* heart
* pathway
|full-text-url=https://sci-hub.do/10.1016/j.molmed.2016.02.007
}}
{{medline-entry
|title=Genotype-phenotype heterogeneity of ganglion cell and inner plexiform layer deficit in autosomal-dominant optic atrophy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26385429
|abstract=To describe the thickness of the combined ganglion cell and inner plexiform layers ([[GC]]-IPL) and the peripapillary retinal nerve fibre layer (RNFL) in patients with [[OPA1]] c.983A>G or c.2708_2711delTTAG autosomal-dominant optic atrophy (ADOA). The study included 20 individuals with c.983A>G and nine individuals with c.2708_2711delTTAG. Data for comparison were drawn from 49, previously published, individuals with [[OPA1]] c.2826_2836delinsGGAT[[GC]]TCCA and 51 individuals with no [[OPA1]] mutation. Subjects underwent refraction, best-corrected visual acuity assessment, axial length measurement and high-definition optical coherence tomography. There was overlap in [[GC]]-IPL thickness in subjects younger than 20-30 years between the two new groups of ADOA patients and controls. Numerical decreases in [[GC]]-IPL thickness with age did not reach statistical significance in individuals with c.983A>G (p = 0.18) or in healthy controls (p = 0.22), but it did in individuals with c.2708_2711delTTAG (p = 0.02). Visual acuity decreased with decreasing [[GC]]-IPL thickness (p = 0.0006 in c.983A>G and p = 0.0084 in c.2708_2711delTTAG). Unlike c.2826_2836delinsGGAT[[GC]]TCCA, individuals with c.983A>G or c.2708_2711delTTAG did not show a pattern of maximum [[GC]]-IPL deficit inferonasal of the fovea. Genotype-phenotype heterogeneity in [[OPA1]] ADOA is evident when inner retinal atrophy is examined as a function of age. Thus, a pronounced decline with age in [[GC]]-IPL thickness is observed in c.2708_2711delTTAG ADOA, an intermediate decline with age is observed in c.983A>G ADOA, whereas little or no change with age is observed in c.2826_2836delinsGGAT[[GC]]TCCA ADOA. This genotype-phenotype heterogeneity may explain why some patients have progressive visual loss while others have a relatively stable prognosis.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aging
* Axial Length, Eye
* Child
* Cross-Sectional Studies
* Female
* GTP Phosphohydrolases
* Genetic Association Studies
* Humans
* Male
* Middle Aged
* Nerve Fibers
* Optic Atrophy, Autosomal Dominant
* Polymorphism, Single Nucleotide
* Retinal Ganglion Cells
* Tomography, Optical Coherence
* Visual Acuity
|keywords=* autosomal-dominant optic atrophy
* dominant optic atrophy
* ganglion cell layer thickness
* retinal nerve fibre layer thickness
|full-text-url=https://sci-hub.do/10.1111/aos.12835
}}
{{medline-entry
|title=Ontogeny of muscle bioenergetics in Adelie penguin chicks (Pygoscelis adeliae).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24005252
|abstract=The ontogeny of pectoralis muscle bioenergetics was studied in growing Adélie penguin chicks during the first month after hatching and compared with adults using permeabilized fibers and isolated mitochondria. With pyruvate-malate-succinate or palmitoyl-carnitine as substrates, permeabilized fiber respiration markedly increased during chick growth (3-fold) and further rose in adults (1.4-fold). Several markers of muscle fiber oxidative activity (cytochrome oxidase, citrate synthase, hydroxyl-acyl-CoA dehydrogenase) increased 6- to 19-fold with age together with large rises in intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial content (3- to 5-fold) and oxidative activities (1.5- to 2.4-fold). The proportion of IMF relative to SS mitochondria increased with chick age but markedly dropped in adults. Differences in oxidative activity between mitochondrial fractions were reduced in adults compared with hatched chicks. Extrapolation of mitochondrial to muscle respirations revealed similar figures with isolated mitochondria and permeabilized fibers with carbohydrate-derived but not with lipid-derived substrates, suggesting diffusion limitations of lipid substrates with permeabilized fibers. Two immunoreactive fusion proteins, mitofusin 2 (Mfn2) and optic atrophy 1 ([[OPA1]]), were detected by Western blots on mitochondrial extracts and their relative abundance increased with age. Muscle fiber respiration was positively related with Mfn2 and [[OPA1]] relative abundance. Present data showed by two complementary techniques large ontogenic increases in muscle oxidative activity that may enable birds to face thermal emancipation and growth in childhood and marine life in adulthood. The concomitant rise in mitochondrial fusion protein abundance suggests a role of mitochondrial networks in the skeletal muscle processes of bioenergetics that enable penguins to overcome harsh environmental constraints.
|mesh-terms=* Age Factors
* Aging
* Animals
* Animals, Newborn
* Avian Proteins
* Cell Respiration
* Electron Transport Complex IV
* Energy Metabolism
* GTP Phosphohydrolases
* Mitochondria, Muscle
* Mitochondrial Dynamics
* Mitochondrial Proteins
* Muscle Fibers, Skeletal
* Pectoralis Muscles
* Spheniscidae
* Weight Gain
|keywords=* fusion proteins
* growth
* isolated mitochondria
* mitofusin
* permeabilized fibers
|full-text-url=https://sci-hub.do/10.1152/ajpregu.00137.2013
}}
{{medline-entry
|title=N-terminal cleavage of the mitochondrial fusion GTPase [[OPA1]] occurs via a caspase-independent mechanism in cerebellar granule neurons exposed to oxidative or nitrosative stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23220553
|abstract=Neuronal cell death via apoptosis or necrosis underlies several devastating neurodegenerative diseases associated with aging. Mitochondrial dysfunction resulting from oxidative or nitrosative stress often acts as an initiating stimulus for intrinsic apoptosis or necrosis. These events frequently occur in conjunction with imbalances in the mitochondrial fission and fusion equilibrium, although the cause and effect relationships remain elusive. Here, we demonstrate in primary rat cerebellar granule neurons (CGNs) that oxidative or nitrosative stress induces an N-terminal cleavage of optic atrophy-1 ([[OPA1]]), a dynamin-like GTPase that regulates mitochondrial fusion and maintenance of cristae architecture. This cleavage event is indistinguishable from the N-terminal cleavage of [[OPA1]] observed in CGNs undergoing caspase-mediated apoptosis (Loucks et al., 2009) and results in removal of a key lysine residue (K301) within the GTPase domain. [[OPA1]] cleavage in CGNs occurs coincident with extensive mitochondrial fragmentation, disruption of the microtubule network, and cell death. In contrast to [[OPA1]] cleavage induced in CGNs by removing depolarizing extracellular potassium (5K apoptotic conditions), oxidative or nitrosative stress-induced [[OPA1]] cleavage caused by complex I inhibition or nitric oxide, respectively, is caspase-independent. N-terminal cleavage of [[OPA1]] is also observed in vivo in aged rat and mouse midbrain and hippocampal tissues. We conclude that N-terminal cleavage and subsequent inactivation of [[OPA1]] may be a contributing factor in the neuronal cell death processes underlying neurodegenerative diseases, particularly those associated with aging. Furthermore, these data suggest that [[OPA1]] cleavage is a likely convergence point for mitochondrial dysfunction and imbalances in mitochondrial fission and fusion induced by oxidative or nitrosative stress.
|mesh-terms=* Aging
* Animals
* Caspases
* Cell Death
* Cells, Cultured
* Cerebellum
* Female
* GTP Phosphohydrolases
* Hippocampus
* MAP Kinase Signaling System
* Male
* Mesencephalon
* Mice
* Mitochondrial Dynamics
* Neurons
* Nitric Oxide
* Oxidative Stress
* Rats
* Rats, Sprague-Dawley
* Reactive Nitrogen Species
* Reactive Oxygen Species

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575199
}}