scholarly journals Aging and Mitochondrial DNA

2010 ◽  
Vol 3 (1) ◽  
pp. 177 ◽  
Author(s):  
P. Das ◽  
G. Guha
Keyword(s):  
Mitochondrial Dna ◽  
Functional Decline ◽  
Oxygen Species ◽  
Degenerative Diseases ◽  
Mtdna Mutations ◽  
Wide Acceptance ◽  
Age Related ◽  
Transport Chain ◽  
Theory Of Aging ◽  
Cellular Pathology

According to the mitochondrial theory of aging, accrual of mutations in mitochondrial DNA (mtDNA) plays the paramount function in the cellular pathology of aging and in development of age-related degenerative ailments. Reactive oxygen species (ROS), which are byproducts of oxidative phosphorylation (OX-PHOS) in aerobic (mitochondrial) respiration, cause oxidative stress-induced damage to mtDNA. This damaged DNA, whose normal role is to encode proteins many of which are players in the electron transport chain (ETC), now codes for defective proteins. Such faulty proteins lead to a considerable impairment in the efficacy of ETC, thereby generating more ROS, which cause further damage to mtDNA in turn, leading to further defects in proteins, aggravated ETC dysfunction, and even more ROS. Hence, a ‘vicious cycle’ propagates that ultimately directs tissue cells towards structural and functional decline, or in other words, degeneration and aging. However, in spite of a wide acceptance of this theory, there have simultaneously been a considerable number of criticisms against it. This review is aimed at discussing the paradigm of aging and degenerative diseases in light of the mitochondrial paraphernalia, with reference to the evidences in support as well as in antagonism to the mitochondrial theory of aging.Keywords: Aging; Degenerative diseases; mtDNA mutations; ROS; Cell death.© 2011 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi:10.3329/jsr.v3i1.5078                J. Sci. Res. 3 (1), 176-186 (2011)

Oxidative Stress, Mitochondrial DNA Mutation, and Impairment of Antioxidant Enzymes in Aging

2002 ◽  
Vol 227 (9) ◽  
pp. 671-682 ◽  
Author(s):  
Yau-Huei Wei ◽  
Hsin-Chen Lee
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Antioxidant Enzymes ◽  
Oxidative Damage ◽  
Large Scale ◽  
Wide Spectrum ◽  
Radical Scavenging ◽  
Mtdna Mutations ◽  
Enhanced Production ◽  
Age Related

Mitochondria do not only produce less ATP, but they also increase the production of reactive oxygen species (ROS) as byproducts of aerobic metabolism in the aging tissues of the human and animals. It is now generally accepted that aging-associated respiratory function decline can result in enhanced production of ROS in mitochondria. Moreover, the activities of free radical-scavenging enzymes are altered in the aging process. The concurrent age-related changes of these two systems result in the elevation of oxidative stress in aging tissues. Within a certain concentration range, ROS may induce stress response of the cells by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell. However, beyond the threshold, ROS may cause a wide spectrum of oxidative damage to various cellular components to result in cell death or elicit apoptosis by induction of mitochondrial membrane permeability transition and release of apoptogenic factors such as cytochrome c. Moreover, oxidative damage and large-scale deletion and duplication of mitochondrial DNA (mtDNA) have been found to increase with age in various tissues of the human. Mitochondria act like a biosensor of oxidative stress and they enable cell to undergo changes in aging and age-related diseases. On the other hand, it has recently been demonstrated that impairment in mitochondrial respiration and oxidative phosphorylation elicits an increase in oxidative stress and causes a host of mtDNA rearrangements and deletions. Here, we review work done in the past few years to support our view that oxidative stress and oxidative damage are a result of concurrent accumulation of mtDNA mutations and defective antioxidant enzymes in human aging.

scholarly journals Mitochondria, oxidative stress and aging

2014 ◽  
Vol 155 (12) ◽  
pp. 447-452
Author(s):  
András Szarka ◽  
Gábor Bánhegyi ◽  
Balázs Sümegi
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Dna ◽  
Mitochondrial Respiration ◽  
Accelerated Aging ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Vicious Cycle ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Theory Of Aging

The free radical theory of aging was defined in the 1950s. On the base of this theory, the reactive oxygen species formed in the metabolic pathways can play pivotal role in ageing. The theory was modified by defining the mitochondrial respiration as the major cellular source of reactive oxygen species and got the new name mitochondrial theory of aging. Later on the existence of a “vicious cycle” was proposed, in which the reactive oxygen species formed in the mitochondrial respiration impair the mitochondrial DNA and its functions. The formation of reactive oxygen species are elevated due to mitochondrial dysfunction. The formation of mitochondrial DNA mutations can be accelerated by this “vicious cycle”, which can lead to accelerated aging. The exonuclease activity of DNA polymerase γ, the polymerase responsible for the replication of mitochondrial DNA was impaired in mtDNA mutator mouse recently. The rate of somatic mutations in mitochondrial DNA was elevated and an aging phenotype could have been observed in these mice. Surprisingly, no oxidative impairment neither elevated reactive oxygen species formation could have been observed in the mtDNA mutator mice, which may question the existence of the “vicious cycle”. Orv. Hetil., 2014, 155(12), 447–452.

scholarly journals What cost mitochondria? The maintenance of functional mitochondrial DNA within and across generations

2014 ◽  
Vol 369 (1646) ◽  
pp. 20130438 ◽  
Author(s):  
Duur K. Aanen ◽  
Johannes N. Spelbrink ◽  
Madeleine Beekman
Keyword(s):  
Mitochondrial Dna ◽  
Somatic Growth ◽  
Mtdna Mutations ◽  
Specific Effects ◽  
Age Related ◽  
Mtdna Replication ◽  
Mtdna Evolution ◽  
Selection For ◽  
Male Specific ◽  
Mtdna Variants

The peculiar biology of mitochondrial DNA (mtDNA) potentially has detrimental consequences for organismal health and lifespan. Typically, eukaryotic cells contain multiple mitochondria, each with multiple mtDNA genomes. The high copy number of mtDNA implies that selection on mtDNA functionality is relaxed. Furthermore, because mtDNA replication is not strictly regulated, within-cell selection may favour mtDNA variants with a replication advantage, but a deleterious effect on cell fitness. The opportunities for selfish mtDNA mutations to spread are restricted by various organism-level adaptations, such as uniparental transmission, germline mtDNA bottlenecks, germline selection and, during somatic growth, regular alternation between fusion and fission of mitochondria. These mechanisms are all hypothesized to maintain functional mtDNA. However, the strength of selection for maintenance of functional mtDNA progressively declines with age, resulting in age-related diseases. Furthermore, organismal adaptations that most probably evolved to restrict the opportunities for selfish mtDNA create secondary problems. Owing to predominantly maternal mtDNA transmission, recombination among mtDNA from different individuals is highly restricted or absent, reducing the scope for repair. Moreover, maternal inheritance precludes selection against mtDNA variants with male-specific effects. We finish by discussing the consequences of life-history differences among taxa with respect to mtDNA evolution and make a case for the use of microorganisms to experimentally manipulate levels of selection.

scholarly journals Mitochondrial Genome (mtDNA) Mutations that Generate Reactive Oxygen Species

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 392 ◽  
Author(s):  
Hahn ◽  
Zuryn
Keyword(s):  
Reactive Oxygen Species ◽  
Neurodegenerative Disorders ◽  
Metabolic Diseases ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cellular Energy ◽  
Mtdna Mutations ◽  
Cellular Energy Metabolism ◽  
Age Related ◽  
Multiple Copies

Mitochondria are critical for the energetic demands of virtually every cellular process within nucleated eukaryotic cells. They harbour multiple copies of their own genome (mtDNA), as well as the protein-synthesing systems required for the translation of vital subunits of the oxidative phosphorylation machinery used to generate adenosine triphosphate (ATP). Molecular lesions to the mtDNA cause severe metabolic diseases and have been proposed to contribute to the progressive nature of common age-related diseases such as cancer, cardiomyopathy, diabetes, and neurodegenerative disorders. As a consequence of playing a central role in cellular energy metabolism, mitochondria produce reactive oxygen species (ROS) as a by-product of respiration. Here we review the evidence that mutations in the mtDNA exacerbate ROS production, contributing to disease.

scholarly journals Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck

2007 ◽  
Vol 104 (18) ◽  
pp. 7540-7545 ◽  
Author(s):  
Shaoyu Zhou ◽  
Sushant Kachhap ◽  
Wenyue Sun ◽  
Guojun Wu ◽  
Alice Chuang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Dna ◽  
Head And Neck ◽  
Squamous Cell ◽  
Reactive Oxygen Species Production ◽  
Oxygen Species ◽  
Mitochondrial Mutations ◽  
Mtdna Mutations ◽  
Coding Regions ◽  
Species Production

Mitochondrial genomic mutations are found in a variety of human cancers; however, the frequency of mitochondrial DNA (mtDNA) mutations in coding regions remains poorly defined, and the functional effects of mitochondrial mutations found in primary human cancers are not well described. Using MitoChip, we sequenced the whole mitochondrial genome in 83 head and neck squamous cell carcinomas. Forty-one of 83 (49%) tumors contained mtDNA mutations. Mutations occurred within noncoding (D-loop) and coding regions. A nonrandom distribution of mutations was found throughout the mitochondrial enzyme complex components. Sequencing of margins with dysplasia demonstrated an identical nonconservative mitochondrial mutation (A76T in ND4L) as the tumor, suggesting a role of mtDNA mutation in tumor progression. Analysis of p53 status showed that mtDNA mutations correlated positively with p53 mutations (P < 0.002). To characterize biological function of the mtDNA mutations, we cloned NADH dehydrogenase subunit 2 (ND2) mutants based on primary tumor mutations. Expression of the nuclear-transcribed, mitochondrial-targeted ND2 mutants resulted in increased anchorage-dependent and -independent growth, which was accompanied by increased reactive oxygen species production and an aerobic glycolytic metabolic phenotype with hypoxia-inducible factor (HIF)-1α induction that is reversible by ascorbate. Cancer-specific mitochondrial mutations may contribute to development of a malignant phenotype by direct genotoxic effects from increased reactive oxygen species production as well as induction of aerobic glycolysis and growth promotion.

scholarly journals Age-related hearing loss and its association with reactive oxygen species and mitochondrial DNA damage

2004 ◽  
Vol 124 (0) ◽  
pp. 16-24 ◽  
Author(s):  
Michael Seidman ◽  
Nadir Ahmad ◽  
Dipa Joshi ◽  
Jake Seidman ◽  
Sujatha Thawani ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Hearing Loss ◽  
Mitochondrial Dna ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Mitochondrial Dna Damage ◽  
Age Related ◽  
Age Related Hearing Loss

scholarly journals Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function

2015 ◽  
Vol 26 (4) ◽  
pp. 674-684 ◽  
Author(s):  
Zhe Chen ◽  
Yun Qi ◽  
Stephanie French ◽  
Guofeng Zhang ◽  
Raúl Covian Garcia ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Mtdna Mutation ◽  
Mitochondrial Dna Mutation ◽  
Tissue Specific ◽  
Dna Mutation ◽  
Mtdna Mutations ◽  
Genetic Mosaic ◽  
Age Related

Various human diseases are associated with mitochondrial DNA (mtDNA) mutations, but heteroplasmy—the coexistence of mutant and wild-type mtDNA—complicates their study. We previously isolated a temperature-lethal mtDNA mutation in Drosophila, mt:CoIT300I, which affects the cytochrome c oxidase subunit I (CoI) locus. In the present study, we found that the decrease in cytochrome c oxidase (COX) activity was ascribable to a temperature-dependent destabilization of cytochrome a heme. Consistently, the viability of homoplasmic flies at 29°C was fully restored by expressing an alternative oxidase, which specifically bypasses the cytochrome chains. Heteroplasmic flies are fully viable and were used to explore the age-related and tissue-specific phenotypes of mt:CoIT300I. The proportion of mt:CoIT300I genome remained constant in somatic tissues along the aging process, suggesting a lack of quality control mechanism to remove defective mitochondria containing a deleterious mtDNA mutation. Using a genetic scheme that expresses a mitochondrially targeted restriction enzyme to induce tissue-specific homoplasmy in heteroplasmic flies, we found that mt:CoIT300I homoplasmy in the eye caused severe neurodegeneration at 29°C. Degeneration was suppressed by improving mitochondrial Ca2+ uptake, suggesting that Ca2+ mishandling contributed to mt:CoIT300I pathogenesis. Our results demonstrate a novel approach for Drosophila mtDNA genetics and its application in modeling mtDNA diseases.

scholarly journals GLUTATHIONE DEFICIENCY AND OXIDATIVE STRESS IN AGING: METABOLIC MECHANISM AND TARGETED INTERVENTION

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S416-S416
Author(s):  
Farook Jahoor ◽  
George E Taffet ◽  
Rajagopal V Sekhar
Keyword(s):  
Oxidative Stress ◽  
Free Radical ◽  
Functional Decline ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Isotope Tracer ◽  
Age Related ◽  
Theory Of Aging ◽  
Metabolic Mechanism ◽  
Glutathione Deficiency

Abstract The free-radical theory of aging suggests that age-related functional decline is mediated by increases in free-radical induced oxidative-stress. Cells normally depend on antioxidants for protection against oxidative-stress. Glutathione is the most abundant endogenous intracellular antioxidant protein composed of 3 amino-acids, cysteine, glycine and glutamic-acid, and is known to be deficient in older-humans. We investigated Glutathione kinetics in older humans using a stable-isotope tracer-based approach, and found that compared to younger humans, older-humans had severe Glutathione deficiency as a result of decreased synthesis caused by limited availability of glycine and cysteine, and associated with elevated oxidative-stress. Orally supplementing glycine and cysteine (provided as N-acetylcysteine) at doses of 1.33mmol/kg/d and 0.81mmol/kg/d respectively for 2-weeks corrected their intracellular deficiency, normalized Glutathione synthesis rates and lowered oxidative-stress to levels in younger controls. These results suggest that short-term supplementation of GlyNAC at these doses can successfully correct intracellular Glutathione deficiency in older-humans.

Origins of mtDNA mutations in ageing

2017 ◽  
Vol 61 (3) ◽  
pp. 325-337 ◽  
Author(s):  
Karolina Szczepanowska ◽  
Aleksandra Trifunovic
Keyword(s):  
Reactive Oxygen Species ◽  
High Throughput ◽  
Point Mutations ◽  
Oxygen Species ◽  
Replication Process ◽  
Mtdna Mutations ◽  
Multiple Organs ◽  
Age Related ◽  
Protein Coating ◽  
High Throughput Dna Sequencing

MtDNA mutations are one of the hallmarks of ageing and age-related diseases. It is well established that somatic point mutations accumulate in mtDNA of multiple organs and tissues with increasing age and heteroplasmy is universal in mammals. However, the origin of these mutations remains controversial. The long-lasting hypothesis stating that mtDNA mutations emanate from oxidative damage via a self-perpetuating mechanism has been extensively challenged in recent years. Contrary to this initial ascertainment, mtDNA appears to be well protected from action of reactive oxygen species (ROS) through robust protein coating and endomitochondrial microcompartmentalization. Extensive development of scrupulous high-throughput DNA sequencing methods suggests that an imperfect replication process, rather than oxidative lesions are the main sources of mtDNA point mutations, indicating that mtDNA polymerase γ (POLG) might be responsible for the majority of mtDNA mutagenic events. Here, we summarize the recent knowledge in prevention and defence of mtDNA oxidative lesions and discuss the plausible mechanisms of mtDNA point mutation generation and fixation.

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