Cause or casualty: The role of mitochondrial DNA in aging and age-associated disease (original) (raw)
Aging: A mitochondrial DNA perspective, critical analysis and an update
World journal of experimental medicine, 2014
The mitochondrial theory of aging, a mainstream theory of aging which once included accumulation of mitochondrial DNA (mtDNA) damage by reactive oxygen species (ROS) as its cornerstone, has been increasingly losing ground and is undergoing extensive revision due to its inability to explain a growing body of emerging data. Concurrently, the notion of the central role for mtDNA in the aging process is being met with increased skepticism. Our progress in understanding the processes of mtDNA maintenance, repair, damage, and degradation in response to damage has largely refuted the view of mtDNA as being particularly susceptible to ROS-mediated mutagenesis due to its lack of "protective" histones and reduced complement of available DNA repair pathways. Recent research on mitochondrial ROS production has led to the appreciation that mitochondria, even in vitro, produce much less ROS than previously thought, automatically leading to a decreased expectation of physiologically achi...
Clinical Science, 2004
Among the numerous theories that explain the process of aging, the mitochondrial theory of aging has received the most attention. This theory states that electrons leaking from the ETC (electron transfer chain) reduce molecular oxygen to form O2•− (superoxide anion radicals). O2•−, through both enzymic and non-enzymic reactions, can cause the generation of other ROS (reactive oxygen species). The ensuing state of oxidative stress results in damage to ETC components and mtDNA (mitochondrial DNA), thus increasing further the production of ROS. Ultimately, this ‘vicious cycle’ leads to a physiological decline in function, or aging. This review focuses on recent developments in aging research related to the role played by mtDNA. Both supportive and contradictory evidence is discussed.
Mitochondrial function and mitochondrial DNA maintenance with advancing age
2014
We review the impact of mitochondrial DNA (mtDNA) maintenance and mitochondrial function on the aging process. Mitochondrial function and mtDNA integrity are closely related. In order to create a protective barrier against reactive oxygen and nitrogen species (RONS) attacks and ensure mtDNA integrity, multiple cellular mtDNA copies are packaged together with various proteins in nucleoids. Regulation of antioxidant and RONS balance, DNA base excision repair, and selective degradation of damaged mtDNA copies preserves normal mtDNA quantities. Oxidative damage to mtDNA molecules does not substantially contribute to increased mtDNA mutation frequency; rather, mtDNA replication errors of DNA PolG are the main source of mtDNA mutations. Mitochondrial turnover is the major contributor to maintenance of mtDNA and functionally active mitochondria. Mitochondrial turnover involves mitochondrial biogenesis, mitochondrial dynamics, and selective autophagic removal of dysfunctional mitochondria (i.e., mitophagy). All of these processes exhibit decreased activity during aging and fall under greater nuclear genome control, possibly coincident with the emergence of nuclear genome instability. We suggest that the age-dependent accumulation of mutated mtDNA copies and dysfunctional mitochondria is associated primarily with decreased cellular autophagic and mitophagic activity.
Mitochondrial DNA mutations and ageing
Biochimica et Biophysica Acta (BBA) - General Subjects, 2009
The mechanism by which we age has sparked a huge number of theories, and is an area of intense debate. As the elderly population rises, the importance of elucidating these mechanisms is becoming more apparent as age is the single biggest risk factor for a number of diseases such as cancer, diabetes and neurodegenerative disease. Mitochondrial DNA (MtDNA) mutations have been shown to accumulate in cells and tissues during the ageing process; however the question as to whether these mutations have a causal role in the ageing process remains an area of uncertainty. Here we review the current literature, and discuss the evidence for and against a causal role of mtDNA mutations in ageing and in the pathogenesis of age-related disease.
The Role of mtDNA Mutation and Mitochondrial Dysfunction on the Aging Process
2019
Statement of Research Problem, Question, or Hypothesis Recent anti-aging research has investigated several functions suspected of being responsible for the development of old age, with one being the impact of mutations in the mitochondrial DNA (mtDNA) and subsequent mitochondrial dysfunction on the onset of aging.
Mitochondrial DNA Damage Patterns and Aging: Revising the Evidences for Humans and Mice
Aging and Disease, 2013
A significant body of work, accumulated over the years, strongly suggests that damage in mitochondrial DNA (mtDNA) contributes to aging in humans. Contradictory results, however, are reported in the literature, with some studies failing to provide support to this hypothesis. With the purpose of further understanding the aging process, several models, among which mouse models, have been frequently used. Although important affinities are recognized between humans and mice, differences on what concerns physiological properties, disease pathogenesis as well as life-history exist between the two; the extent to which such differences limit the translation, from mice to humans, of insights on the association between mtDNA damage and aging remains to be established. In this paper we revise the studies that analyze the association between patterns of mtDNA damage and aging, investigating putative alterations in mtDNA copy number as well as accumulation of deletions and of point mutations. Reports from the literature do not allow the establishment of a clear association between mtDNA copy number and age, either in humans or in mice. Further analysis, using a wide spectrum of tissues and a high number of individuals would be necessary to elucidate this pattern. Likewise humans, mice demonstrated a clear pattern of age-dependent and tissuespecific accumulation of mtDNA deletions. Deletions increase with age, and the highest amount of deletions has been observed in brain tissues both in humans and mice. On the other hand, mtDNA point mutations accumulation has been clearly associated with age in humans, but not in mice. Although further studies, using the same methodologies and targeting a larger number of samples would be mandatory to draw definitive conclusions, the revision of the available data raises concerns on the ability of mouse models to mimic the mtDNA damage patterns of humans, a fact with implications not only for the study of the aging process, but also for investigations of other processes in which mtDNA dysfunction is a hallmark, such as neurodegeneration.
Mitochondrial DNA damage and the aging process–facts and imaginations*
Free Radical Research, 2006
Mitochondrial DNA (mtDNA) is a circular double-stranded molecule organized in nucleoids and covered by the histone-like protein mitochondrial transcription factor A (TFAM). Even though mtDNA repair capacity appears to be adequate the accumulation of mtDNA mutations has been shown to be at least one important molecular mechanism of human aging. Reactive oxygen species (ROS), which are generated at the FMN moiety of mitochondrial respiratory chain (RC) complex I, should be considered to be important at least for the generation of age-dependent mtDNA deletions. However, the accumulation of acquired mutations to functionally relevant levels in aged tissues seems to be a consequence of clonal expansions of single founder molecules and not of ongoing mutational events.
MtDNA Deletions in Aging and in Nonmitochondrial Pathologies
Annals of the New York Academy of Sciences, 2006
According to the "mitochondrial theory of aging," the age-related increase in reactive oxygen species (ROS) is responsible for the bioenergetic decay of mitochondria in aging through a mutagenic effect on mitochondrial DNA (mtDNA). 1 Such an effect should be more relevant in nervous tissue and skeletal muscle, which are postmitotic tissues that are highly dependent on oxidative metabolism.
The ageing mitochondrial genome
Nucleic acids research, 2007
The population of elderly individuals has increased significantly over the past century and is predicted to rise even more rapidly in the future. Ageing is a major risk factor for many diseases such as neurodegenerative disease, diabetes and cancer. This highlights the importance of understanding the mechanisms involved in the ageing process. One plausible mechanism for ageing is accumulation of mutations in the mitochondrial genome. In this review, we discuss some of the most convincing data surrounding age-related mtDNA mutations and the evidence that these mutations contribute to the ageing process.