Role Of Mitochondria In Aging Research Articles

New insights into the role of mitochondria in aging: mitochondrial dynamics and more

A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders. A deeper understanding of the intricate nature of mitochondrial dynamics, which is described as the balance between mitochondrial fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important factors in several key pathologies associated with aging. Indeed, a recent wave of studies has demonstrated the pleiotropic role of fusion and fission proteins in numerous cellular processes, including mitochondrial metabolism, redox signaling, the maintenance of mitochondrial DNA and cell death. Additionally, mitochondrial fusion and fission, together with autophagy, have been proposed to form a quality-maintenance mechanism that facilitates the removal of damaged mitochondria from the cell, a process that is particularly important to forestall aging. Thus, dysfunctional regulation of mitochondrial dynamics might be one of the intrinsic causes of mitochondrial dysfunction, which contributes to oxidative stress and cell death during the aging process. In this Commentary, we discuss recent studies that have converged at a consensus regarding the involvement of mitochondrial dynamics in key cellular processes, and introduce a possible link between abnormal mitochondrial dynamics and aging.

The Relationship between the Aging- and Photo-Dependent T414G Mitochondrial DNA Mutation with Cellular Senescence and Reactive Oxygen Species Production in Cultured Skin Fibroblasts

Mutations in the mitochondrial genome (mtDNA) are thought to be one of the causes of age-dependent cellular decline through their detrimental effects on respiration or reactive oxygen species (ROS) production. However, for many mutations, this link has not been clearly established. This study aimed to further investigate the phenotypic importance of a T414G mutation within the control region of mtDNA, previously shown to accumulate in both chronologically and photoaged human skin. We demonstrate that during dermal skin fibroblast replication in vitro in five separate cultures obtained from elderly individuals, the T414G mutant load can either increase or decrease during progressive cell division, implying the absence of consistent selection against the mutation in this context. In support of this, by utilizing a cell-sorting approach, we demonstrate that the level of the T414G mutation does not directly correlate with increased or decreased mtDNA copy number, or markers of cellular ageing including lipofuscin accumulation or ROS production. By consequence, the mutation can be distributed with a bias towards either the proliferating or senescent cell populations depending on the cell line. In conclusion, we propose that this particular mutation may have little effect on ROS production and the onset of cellular senescence in cultured fibroblasts.

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The role of mitochondria in aging of skeletal muscle

Aging can be characterized as a time dependent decline of maximal functionality that affects tissues and organs of the whole body. Such is induced by the progressive loss of redundant components and leads to an increased susceptibility to disease and risk of death. Regarding the aging of skeletal muscle, it has been pointed out that mitochondria is a key factor behind the loss of redundancy and functionality, since this organelle has a major role in cellular homeostasis particularly at the level of the bioenergetic status. Decreased activities of the mitochondrial electron transport chain complexes and an increased release of reactive oxygen species from mitochondria are well documented with age; it is suggested that the mitochondrial loss of function results from the increased oxidative damage to proteins, lipids, and DNA of this organelle. However, it is important to be aware that the mitochondrial loss of function could also be a consequence, rather than a cause, of the cellular deterioration with age, which compromises mitochondrial biogenesis, mitochondrial protein turnover and autophagocytosis of damaged mitochondria. In this review several topics will be addressed regarding the age-related loss of skeletal muscle redundancy associated with mitochondrial dysfunction, emphasizing hypotheses for underlying mechanisms. In addition, we discuss some of the cellular mechanisms that can be pointed out as being responsible for the age-related mitochondrial dysfunction.

Program‐like aging and mitochondria: Instead of random damage by free radicals

As recently suggested, the target of rapamycin (TOR) pathway, rather than molecular damage by free radicals, drives aging and diseases of aging. But may mitochondria nevertheless contribute to aging? Here, I discuss aimless program-like aging (versus altruistic program), conflict between the cell and mitochondria, cell murder (versus cell suicide) and the role of mitochondria in aging. In particular, life-long selection among mitochondria may yield "selfish" (malignant) mitochondria resistant to autophagy. And TOR may create an intra-cellular environment that is permissive for such selfish mitochondria. In theory, pharmacologic inhibitors of the TOR pathway may reverse accumulation of defective mitochondria, while also inhibiting the aging process.

The curiously complex role of mitochondria in ageing

The curiously complex role of mitochondria in ageing

The role of mitochondria in ageing and carcinogenesis

Mitochondria can perform multiple cellular functions including energy production, cell proliferation and apoptosis. These organelles contain their own genetic material, mitochondrial DNA (mtDNA), which is maternally inherited. Although much smaller than the nuclear genome, mtDNA is equally important, as it has been hypothesized to play a crucial role in ageing and carcinogenesis. This is partly due to the fact that mitochondria represent the major site for the generation of cellular oxidative stress and play a key role in mediating programmed cell death (apoptosis). Damage to mtDNA is therefore an important contributor to human ageing, cancer and neurodegenerative diseases. The most relevant footprints of mtDNA damage are point mutations of single bases, or deletions of the 16.5-kb mitochondrial genome. This review will focus on the key roles of mitochondrial function and mtDNA in oxidative stress production and as a mediator of apoptosis, and on the use of mtDNA as a biomarker of sun exposure. This will be related to the contribution of mitochondria and mtDNA in the ageing process and cancer, with a specific focus on human skin. In conclusion, it is likely that the interplay between nuclear and mitochondrial genes may hold the final understanding of the mitochondrial role in these disease processes.

Mitochondrial Genetics of Aging: Intergenomic Conflict Resolution

Mitochondria are the organelles of aerobic respiration. They consume the oxygen we breathe to stay alive and generate energy for cells to function. But oxygen can be dangerous. Indeed, mitochondria generate the majority of reactive oxygen species that are prime suspects among the causes of aging. Mitochondria have been influential elements of evolving eukaryotic cells for perhaps 2 billion years, since a eubacterium fused with an archaebacterium. The picture that has emerged from this long history of genomic fusion is that of a complex network of nuclear-mitochondrial cross-talk. Here, we discuss the biochemical and genetic conflicts between mitochondria and nucleus, which have shaped the role of mitochondria in aging, and point to new paths for further investigations.

MiMage: A Pan-European Project on the Role of Mitochondria in Aging

The new European research project MiMage, supported by the European Community's Sixth Framework for Research and Technological Development, focuses on elucidating the role of mitochondria in conserved mechanisms of aging. Expertise in different research areas, including biochemistry, cell biology, genetics, molecular biology, and physiology, is provided by twelve research teams from seven European countries, together with one associated team from Canada and the United States. This report provides an introduction to the participating laboratories and the topics that will be addressed within the project, together with a concise report on the first symposium on the role of mitochondria in aging.

Mitochondrial dysfunction measured in vivo

Mitochondria are responsible for meeting the majority of the energetic demand of most tissues. They also play a major role in regulating cell survival. These dual roles of mitochondria place them at the centre of many pathologies leading to tissue degeneration and disruption of energy balance. The prominent role of mitochondria in ageing and disease has led to a tremendous growth in mitochondrial research at the cellular and molecular level. We describe below a new non-invasive approach to measure mitochondrial function that will bridge the gap between our understanding of mitochondrial function in vitro and that in the intact organism. This approach uses optical and magnetic resonance spectroscopy to measure in vivo O2 consumption and ATP synthesis rates, respectively, from skeletal muscle. These values lead to a quantitative assessment of the mitochondrial ATP/O2 or P/O. The P/O represents the efficiency of coupling between phosphorylation and oxygen consumption in the mitochondria, which is a measure of mitochondrial dysfunction. This work represents a significant advance in research on the role of mitochondria in degenerative disease and ageing because it allows a quantitative measure of mitochondrial pathology in vivo. The non-invasive nature of this approach also enables repeated measures of mitochondrial function on the same individual, thereby making this a potentially useful diagnostic technique. The results from this work have led to insights into the coupling of ATP synthesis to oxidation and the regulation of oxidative phosphorylation by intracellular PO2.

Aging and oxidative stress: studies of some genes involved both in aging and in response to oxidative stress

Aging is a complex physiological phenomenon and several theories have been developed about its origin. Among such theories, the ‘mitochondrial theory of aging’ has been supported by numerous studies and reviews. Cell oxidative damage, in particular the accumulation of mtDNA mutations, is determined by the rate of reactive oxygen species production and degradation induced by the antioxidant defense systems. In this review, data from our laboratory and from the recent literature have been examined to provide arguments that reinforce the crucial role of mitochondria in aging. Various genes that affect life span have been described in numerous organisms. Some of them encode signal transduction proteins and participate in the regulation of mitochondrial metabolism.

Fragmented mitochondrial DNA is the predominant carrier of oxidized DNA bases.

Previous analyses indicated a high level of oxidative base modification in mitochondrial DNA, the extent of which raised questions about the methodological validity and biological implications. In the present study DNA was isolated from rat liver mitochondria under carefully controlled conditions, and the extent of base oxidation, DNA fragmentation, and nuclear DNA contamination were analyzed. DNA isolated from intact mitochondria treated with DNase consisted of 16.3 kilobase pairs, mostly circular, mitochondrial DNA molecules and a mixture of nuclear and mitochondrial DNA fragments, as identified by agarose gel electrophoresis and hybridization. High-performance liquid chromatography in combination with electrochemical detection confirmed that the overall level of 8-hydroxy-2'-deoxyguanosine, a marker commonly used in the analysis of base oxidation, is higher in mitochondrial than in nuclear DNA. Importantly, 8-hydroxy-2'-deoxyguanosine is relatively scarce in the 16.3 kilobase pair mitochondrial DNA molecules (0.051 pmol/microgram) but is present in high levels in mitochondrial DNA fragments (0.741 pmol/microgram). The fragments constitute about 18% of total mitochondrial DNA. The antitumor agent bleomycin, which binds to DNA, forms an iron complex capable of transferring electrons from Fe2+ to molecular oxygen. Exposure of mitochondria to bleomycin and iron resulted in nicking but not in a significant increase in base oxidation of 16.3 kilobase pair mitochondrial DNA, whereas the amount and the oxidation level of fragmented mitochondrial DNA significantly increased. These findings are relevant for a better understanding of the role of mitochondria in aging and various diseases and are consistent with the notion that despite the overall high DNA oxidation level, mitochondria can faithfully proliferate.

Mitochondrial aging: open questions.

Interest in the role of mitochondria in aging has intensified in recent years. This focus on mitochondria originated in part from the free radical theory of aging, which argues that oxidative damage plays a key role in degenerative senescence. Among the numerous mechanisms known to generate oxidants, leakage of the superoxide anion and hydrogen peroxide from the mitochondrial electron transport chain are of particular interest, due to the correlation between species-specific metabolic rate ("rate of living") and life span. Phenomenological studies of mitochondrial function long ago noted a decline in mitochondrial function with age, and on-going research continues to add to this body of knowledge. The extranuclear somatic mutation theory of aging proposes that the accumulation of mutations in the mitochondrial genome may be responsible in part for the mitochondrial phenomenology of aging. Recent studies of mitochondrial DNA (mtDNA) deletions have shown that they increase with age in humans and other mammals. Currently, there exist numerous important and fundamental questions surrounding mitochondria and aging. Among these are (1) How important are mitochondrial oxidants in determining overall cellular oxidative stress? (2) What are the mechanisms of mitochondrial oxidant generation? (3) How are lesions and mutations in mtDNA formed? (4) How important are mtDNA lesions and mutations in causing mitochondrial dysfunction? (5) How are mitochondria regulated, and how does this regulation change during aging? (6) What are the dynamics of mitochondrial turnover? (7) What is the relationship between mitochondrial damage and lipofuscinogenesis? (8) What are the relationships among mitochondria, apopotosis, and aging? and (9) How can mitochondrial function (ATP generation and the establishment of a membrane potential) and dysfunction (oxidant generation) be modulated and degenerative senescence thereby treated?

Aging and mitochondria

Aging is a complex physiological phenomenon and several different theories have been elaborated about its origin. Among such theories, the ‘mitochondrial theory of aging’, which has gained a large support, indicates the accumulation of somatic mutations of mitochondrial DNA leading to the decline of mitochondrial functionality as one of the driving forces for the process itself. In this review data on rat and man from our laboratory and from recent literature have been thoroughly examined and compared in order to provide the ‘state-of-the-art’ on the role of mitochondria in aging. Alterations of structure and expression of mitochondrial genome with aging, to find out the eventual relevant changes of mitochondrial biogenesis, have been studied in rat whereas the relationship between cytochrome c oxidase activity and ‘common deletion’ has been studied in man. Results on the effect of acetyl-L-carnitine on the mitochondrial functionality are also reported.