Mitochondrial Aging and Age-Related Dysfunction of Mitochondria

Age-related changes in mitochondria are associated with decline in mitochondrial function. With advanced age, mitochondrial DNA volume, integrity and functionality decrease due to accumulation of mutations and oxidative damage induced by reactive oxygen species (ROS). In aged subjects, mitochondria are characterized by impaired function such as lowered oxidative capacity, reduced oxidative phosphorylation, decreased ATP production, significant increase in ROS generation, and diminished antioxidant defense. Mitochondrial biogenesis declines with age due to alterations in mitochondrial dynamics and inhibition of mitophagy, an autophagy process that removes dysfunctional mitochondria. Age-dependent abnormalities in mitochondrial quality control further weaken and impair mitochondrial function. In aged tissues, enhanced mitochondria-mediated apoptosis contributes to an increase in the percentage of apoptotic cells. However, implementation of strategies such as caloric restriction and regular physical training may delay mitochondrial aging and attenuate the age-related phenotype in humans.

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In vivo mitochondrial function in aging skeletal muscle: capacity, flux, and patterns of use

Journal of Applied Physiology ◽

10.1152/japplphysiol.00583.2016 ◽

2016 ◽

Vol 121 (4) ◽

pp. 996-1003 ◽

Cited By ~ 16

Author(s):

Jane A. Kent ◽

Liam F. Fitzgerald

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Mitochondrial Function ◽

Human Skeletal Muscle ◽

Oxidative Capacity ◽

Mitochondrial Content ◽

Atp Production ◽

Age Related ◽

Age Related Changes

Because of the fundamental dependence of mammalian life on adequate mitochondrial function, the question of how and why mitochondria change in old age is the target of intense study. Given the importance of skeletal muscle for the support of mobility and health, this question extends to the need to understand mitochondrial changes in the muscle of older adults, as well. We and others have focused on clarifying the age-related changes in human skeletal muscle mitochondrial function in vivo. These changes include both the maximal capacity for oxidative production of energy (ATP), as well as the relative use of mitochondrial ATP production for powering muscular activity. It has been known for nearly 50 yr that muscle mitochondrial content is highly plastic; exercise training can induce an ∼2-fold increase in mitochondrial content, while disuse has the opposite effect. Here, we suggest that a portion of the age-related changes in mitochondrial function that have been reported are likely the result of behavioral effects, as physical activity influences have not always been accounted for. Further, there is emerging evidence that various muscles may be affected differently by age-related changes in physical activity and movement patterns. In this review, we will focus on age-related changes in oxidative capacity and flux measured in vivo in human skeletal muscle.

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Random errors in protein synthesis activate an age-dependent program of muscle atrophy in mice

Communications Biology ◽

10.1038/s42003-021-02204-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

James Moore ◽

Rashid Akbergenov ◽

Martina Nigri ◽

Patricia Isnard-Petit ◽

Amandine Grimm ◽

...

Keyword(s):

Protein Synthesis ◽

Muscle Atrophy ◽

Strength Analysis ◽

Dependent Manner ◽

Random Errors ◽

Age Related ◽

Related Phenotype ◽

Age Dependent ◽

Translation Accuracy ◽

Transcriptomic Changes

AbstractRandom errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. Here, we studied whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of mammalian translation, if at all viable, present any specific, possibly aging-related, phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic and showed a muscle-related phenotype with reduced grip strength. Analysis of gene expression in skeletal muscle using RNA-Seq revealed transcriptomic changes occurring in an age-dependent manner, involving an interplay of PGC1α, FOXO3, mTOR, and glucocorticoids as key signaling pathways, and finally resulting in activation of a muscle atrophy program. Our results highlight the relevance of translation accuracy, and show how disturbances thereof may contribute to age-related pathologies.

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Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems

International Journal of Molecular Sciences ◽

10.3390/ijms21207698 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7698 ◽

Cited By ~ 1

Author(s):

Peter Kaplan ◽

Zuzana Tatarkova ◽

Monika Kmetova Sivonova ◽

Peter Racay ◽

Jan Lehotsky

Keyword(s):

Antioxidant Defense ◽

Current Knowledge ◽

Mitochondrial Dynamics ◽

Ros Generation ◽

Elevated Concentration ◽

Apoptotic Pathway ◽

Beneficial Effects ◽

Mitochondrial Ros ◽

Mitochondrial Functions ◽

Altered Gene

Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and neurodegenerative diseases. Accumulating evidence indicates that pathophysiology of these diseases is linked with mitochondrial dysfunction. In this review, we discuss the current knowledge concerning the effects of HHcy on mitochondrial homeostasis, including energy metabolism, mitochondrial apoptotic pathway, and mitochondrial dynamics. The recent studies suggest that the interaction between Hcy and mitochondria is complex, and reactive oxygen species (ROS) are possible mediators of Hcy effects. We focus on mechanisms contributing to HHcy-associated oxidative stress, such as sources of ROS generation and alterations in antioxidant defense resulting from altered gene expression and post-translational modifications of proteins. Moreover, we discuss some recent findings suggesting that HHcy may have beneficial effects on mitochondrial ROS homeostasis and antioxidant defense. A better understanding of complex mechanisms through which Hcy affects mitochondrial functions could contribute to the development of more specific therapeutic strategies targeted at HHcy-associated disorders.

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Mitochondrial Dynamics and VMP1-Related Selective Mitophagy in Experimental Acute Pancreatitis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.640094 ◽

2021 ◽

Vol 9 ◽

Author(s):

Virginia Vanasco ◽

Alejandro Ropolo ◽

Daniel Grasso ◽

Diego S. Ojeda ◽

María Noé García ◽

...

Keyword(s):

Acute Pancreatitis ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Cell Model ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Pancreatic Acinar Cells ◽

Atp Production ◽

Selective Autophagy ◽

Mild Disease

Mitophagy and zymophagy are selective autophagy pathways early induced in acute pancreatitis that may explain the mild, auto limited, and more frequent clinical presentation of this disease. Adequate mitochondrial bioenergetics is necessary for cellular restoration mechanisms that are triggered during the mild disease. However, mitochondria and zymogen contents are direct targets of damage in acute pancreatitis. Cellular survival depends on the recovering possibility of mitochondrial function and efficient clearance of damaged mitochondria. This work aimed to analyze mitochondrial dynamics and function during selective autophagy in pancreatic acinar cells during mild experimental pancreatitis in rats. Also, using a cell model under the hyperstimulation of the G-coupled receptor for CCK (CCK-R), we aimed to investigate the mechanisms involved in these processes in the context of zymophagy. We found that during acute pancreatitis, mitochondrial O2consumption and ATP production significantly decreased early after induction of acute pancreatitis, with a consequent decrease in the ATP/O ratio. Mitochondrial dysfunction was accompanied by changes in mitochondrial dynamics evidenced by optic atrophy 1 (OPA-1) and dynamin-related protein 1 (DRP-1) differential expression and ultrastructural features of mitochondrial fission, mitochondrial elongation, and mitophagy during the acute phase of experimental mild pancreatitis in rats. Mitophagy was also evaluated by confocal assay after transfection with the pMITO-RFP-GFP plasmid that specifically labels autophagic degradation of mitochondria and the expression and redistribution of the ubiquitin ligase Parkin1. Moreover, we report for the first time that vacuole membrane protein-1 (VMP1) is involved and required in the mitophagy process during acute pancreatitis, observable not only by repositioning around specific mitochondrial populations, but also by detection of mitochondria in autophagosomes specifically isolated with anti-VMP1 antibodies as well. Also, VMP1 downregulation avoided mitochondrial degradation confirming that VMP1 expression is required for mitophagy during acute pancreatitis. In conclusion, we identified a novel DRP1-Parkin1-VMP1 selective autophagy pathway, which mediates the selective degradation of damaged mitochondria by mitophagy in acute pancreatitis. The understanding of the molecular mechanisms involved to restore mitochondrial function, such as mitochondrial dynamics and mitophagy, could be relevant in the development of novel therapeutic strategies in acute pancreatitis.

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Age-related changes in ATP-producing pathways in human skeletal muscle in vivo

Journal of Applied Physiology ◽

10.1152/japplphysiol.00566.2005 ◽

2005 ◽

Vol 99 (5) ◽

pp. 1736-1744 ◽

Cited By ~ 124

Author(s):

Ian R. Lanza ◽

Douglas E. Befroy ◽

Jane A. Kent-Braun

Keyword(s):

Skeletal Muscle ◽

Oxidative Phosphorylation ◽

Atp Synthesis ◽

Older Men ◽

Oxidative Capacity ◽

Glycolytic Flux ◽

Synthesis Rate ◽

Anaerobic Glycolysis ◽

Atp Production ◽

Age Related

Energy for muscle contractions is supplied by ATP generated from 1) the net hydrolysis of phosphocreatine (PCr) through the creatine kinase reaction, 2) oxidative phosphorylation, and 3) anaerobic glycolysis. The effect of old age on these pathways is unclear. The purpose of this study was to examine whether age may affect ATP synthesis rates from these pathways during maximal voluntary isometric contractions (MVIC). Phosphorus magnetic resonance spectroscopy was used to assess high-energy phosphate metabolite concentrations in skeletal muscle of eight young (20–35 yr) and eight older (65–80 yr) men. Oxidative capacity was assessed from PCr recovery after a 16-s MVIC. We determined the contribution of each pathway to total ATP synthesis during a 60-s MVIC. Oxidative capacity was similar across age groups. Similar rates of ATP synthesis from PCr hydrolysis and oxidative phosphorylation were observed in young and older men during the 60-s MVIC. Glycolytic flux was higher in young than older men during the 60-s contraction ( P < 0.001). When expressed relative to the overall ATP synthesis rate, older men relied on oxidative phosphorylation more than young men ( P = 0.014) and derived a smaller proportion of ATP from anaerobic glycolysis ( P < 0.001). These data demonstrate that although oxidative capacity was unaltered with age, peak glycolytic flux and overall ATP production from anaerobic glycolysis were lower in older men during a high-intensity contraction. Whether this represents an age-related limitation in glycolytic metabolism or a preferential reliance on oxidative ATP production remains to be determined.

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Exercise rescues mitochondrial coupling in aged skeletal muscle: a comparison of different modalities in preventing sarcopenia

Journal of Translational Medicine ◽

10.1186/s12967-021-02737-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Colin Harper ◽

Venkatesh Gopalan ◽

Jorming Goh

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Function ◽

Fiber Type ◽

Skeletal Muscle Function ◽

Atp Production ◽

Muscle Aging ◽

Age Related ◽

Key Factor ◽

Underlying Mechanisms ◽

Skeletal Muscle Aging

AbstractSkeletal muscle aging is associated with a decline in motor function and loss of muscle mass- a condition known as sarcopenia. The underlying mechanisms that drive this pathology are associated with a failure in energy generation in skeletal muscle, either from age-related decline in mitochondrial function, or from disuse. To an extent, lifelong exercise is efficacious in preserving the energetic properties of skeletal muscle and thus may delay the onset of sarcopenia. This review discusses the cellular and molecular changes in skeletal muscle mitochondria during the aging process and how different exercise modalities work to reverse these changes. A key factor that will be described is the efficiency of mitochondrial coupling—ATP production relative to O2 uptake in myocytes and how that efficiency is a main driver for age-associated decline in skeletal muscle function. With that, we postulate the most effective exercise modality and protocol for reversing the molecular hallmarks of skeletal muscle aging and staving off sarcopenia. Two other concepts pertinent to mitochondrial efficiency in exercise-trained skeletal muscle will be integrated in this review, including- mitophagy, the removal of dysfunctional mitochondrial via autophagy, as well as the implications of muscle fiber type changes with sarcopenia on mitochondrial function.

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Mitochondrial Function, Mobility and Lifespan Are Improved in Drosophila melanogaster by Extracts of 9-cis-β-Carotene from Dunaliella salina

Marine Drugs ◽

10.3390/md17050279 ◽

2019 ◽

Vol 17 (5) ◽

pp. 279 ◽

Cited By ~ 2

Author(s):

Tobias Weinrich ◽

Yanan Xu ◽

Chiziezi Wosu ◽

Patricia J. Harvey ◽

Glen Jeffery

Keyword(s):

Drosophila Melanogaster ◽

Mitochondrial Function ◽

Dunaliella Salina ◽

Whole Body ◽

Biological Impact ◽

Atp Production ◽

Beneficial Effects ◽

Positive Effects ◽

Age Related ◽

Β Carotene

Carotenoids are implicated in alleviating ageing and age-related diseases in humans. While data from different carotenoids are mixed in their outcomes, those for 9-cis-β-carotene indicate general positive effects, although basic data on its biological impact are limited. Here, we show that supplementation with 9-cis-β-carotene in ageing Drosophila melanogaster improved mitochondrial function in terms of ATP production and whole-body respiration and extended mean lifespan. It also resulted in improved mobility. These data provide a potential biological rational for the beneficial effects of dietary supplementation with 9-cis-β-carotene. These effects may be based on the maintenance of a sound mitochondrial function.

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Drosophila Prominin-like, a homolog of CD133, interacts with ND20 to maintain mitochondrial function

Cell & Bioscience ◽

10.1186/s13578-019-0365-0 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Xuexiang Wang ◽

Huimei Zheng ◽

Zexiao Jia ◽

Zhaoying Lei ◽

Mengyao Li ◽

...

Keyword(s):

Mitochondrial Function ◽

Ros Generation ◽

Mitochondrial Dysfunctions ◽

Atp Production ◽

Transmembrane Glycoprotein ◽

Transport Chain ◽

Mitochondrial Respiratory Complex ◽

A Subunit ◽

Respiratory Complex I ◽

Two Hybrid

Abstract Background Drosophila Prominin-like is a homolog of mammalian CD133, which is recognized as a biomarker for stem cells. The interacting proteins of CD133 and their biological functions remain elusive. Results In this study, we using yeast two-hybrid assays, GST pull-down assay and co-immunoprecipitation (Co-IP) methods found that Drosophila Prominin-like interacts with ND20, a subunit of mitochondrial respiratory complex I. Bioinformatics analysis suggests that Prominin-like is a six-transmembrane glycoprotein which localizes on cellular membranes. Immunostaining and mitochondrial fractionation indicate that Drosophila Prominin-like could localize in the mitochondria. The knockdown of prominin-like in S2 cells resulted in transient mitochondrial dysfunctions as evidenced by reduced ATP production, elevated ROS generation and an accompanied reduction in mitochondrial proteins. Mitochondrial dysfunctions were detected in aged prominin-like mutant flies. Conclusion Our data indicates that Prominin-like acts to maintain mitochondrial function through its interaction with ND20 which, itself, is active in the mitochondrial electron transport chain. Our study provides insights into a novel molecular mechanism of Drosophila prominin-like and suggests a similar function of CD133 in mammals.

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Endothelial cells maintain a reduced redox environment even as mitochondrial function declines

AJP Cell Physiology ◽

10.1152/ajpcell.00092.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. C1675-C1686 ◽

Cited By ~ 7

Author(s):

Ricarda Carlisle ◽

Carol Ann Rhoads ◽

Tak Yee Aw ◽

Lynn Harrison

Keyword(s):

Endothelial Cells ◽

Oxygen Consumption ◽

Genomic Instability ◽

Mitochondrial Function ◽

Replicative Senescence ◽

Umbilical Vein ◽

Nuclear Genome ◽

Mitochondrial Mass ◽

Atp Production ◽

Age Related

Human umbilical vein endothelial cells (HUVECs) are an endothelial model of replicative senescence. Oxidative stress, possibly due to dysfunctional mitochondria, is believed to play a key role in replicative senescence and atherosclerosis, an age-related vascular disease. In this study, we determined the effect of cell division on genomic instability, mitochondrial function, and redox status in HUVECs that were able to replicate for ∼60 cumulative population doublings (CPD). After 20 CPD, the nuclear genome deteriorated and the protein content of the cell population increased. This indicated an increase in cell size, which was accompanied by an increase in oxygen consumption, ATP production, and mitochondrial genome copy number and ∼10% increase in mitochondrial mass. The antioxidant capacity increased, as seen by an increase in reduced glutathione, glutathione peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase. However, by CPD 52, the latter two enzymes decreased, as well as the ratio of mitochondrial-to-nuclear genome copies, the mitochondrial mass, and the oxygen consumption per milligram of protein. Our results signify that HUVECs maintain a highly reducing (GSH) environment as they replicate despite genomic instability and loss of mitochondrial function.

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TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction

Cellular Physiology and Biochemistry ◽

10.1159/000430174 ◽

2015 ◽

Vol 36 (5) ◽

pp. 2072-2082 ◽

Cited By ~ 21

Author(s):

Peng Zhang ◽

Yong Lu ◽

Dong Yu ◽

Dadong Zhang ◽

Wei Hu

Keyword(s):

Cell Death ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Ros Generation ◽

Complex Activity ◽

Atp Production

Background: Tumor necrosis factor receptor-associated protein 1 (TRAP1), an essential mitochondrial chaperone is induced in rat hearts following ischemia/reperfusion (I/R), but its role in myocardial I/R injury is unclear. The present study examined the function of TRAP1 in cardiomyocyte hypoxia/reoxygenation injury in vitro and myocardial I/R injury in vivo. Methods: HL-1 cardiomyocytes transfected with TRAP1 or vector were subjected to simulated I/R (SI/R) in vitro. Cell death and mitochondrial function were assessed. Wild type (WT) and TRAP1 knockout (TRAP1 KO) mice were subjected to cardiac I/R in vivo. The infarct size and myocardial apoptosis were determined. WT and TRAP1 KO cardiomyocytes were subjected to SI/R in vitro. Mitochondrial function was assessed. Results: TRAP1 overexpression protects HL-1 cardiomyocytes from SI/R-induced cell death in vitro. The reduced cell death was associated with decreased ROS generation, better-preserved mitochondrial ETC complex activity, membrane potential, and ATP production, as well as delayed mPTP opening. Loss of TRAP1 aggravates SI/R-induced mitochondrial damage in cardiomyocytes in vitro and myocardial I/R injury and apoptosis in vivo. Conclusion: The results of the present study show that TRAP1 provides cardioprotection against myocardial I/R by ameliorating mitochondrial dysfunction.

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