Chapter Two - Mitochondrial DNA Mutations in Aging

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Abstract

The relationship of mitochondrial DNA mutations to aging is still debated. Most mtDNA mutations are recessive: there are multiple copies per cell and mutation needs to clonally expand to cause respiratory deficiency. Overall mtDNA mutant loads are low, so effects of mutations are limited to critical areas where mutations locally reach high fractions. This includes respiratory chain deficient zones in muscle fibers, respiratory-deficient crypts in colon, and massive expansions of deleted mtDNA in substantia nigra neurons. mtDNA “mutator” mouse with increased rate of mtDNA mutations is a useful model, although rates and distribution of mutations may significantly deviate from what is observed in human aging. Comparison of species with different longevity reveals intriguing longevity-related traits in mtDNA sequence, although their significance is yet to be evaluated. The impact of somatic mtDNA mutations rapidly increases with age, so their importance is expected to grow as human life expectancy increases.

Section snippets

Introduction: The Different Faces of the Mitochondrial Theory of Aging

Mitochondrial involvement in aging was proposed over 30 years ago by Denham Harman, based on his original theory that aging is caused by the accumulation of damage resulting from reactive oxygen species (ROS).1 ROS are the inevitable by-products of normal cellular processes, most notably the process of oxidative phosphorylation, which is the primary function of the mitochondrion. Harman noted that as a major source of ROS, mitochondria should also be its major target.1 Hence, as the part of the

Mitochondrial biology and mtDNA

Mitochondria are subcellular organelles responsible for generation of ATP, the cell's universal energy carrier, in a process of oxidative phosphorylation. This process is performed by a set of five multisubunit enzyme complexes (I, II, III, IV, and V) called the respiratory chain (RC), which are located on the inner membrane of the mitochondrion (for illustration see Ref. 5). Depending on the metabolic requirement of the cell, the number of mitochondria can vary markedly. In the majority of

RC deficiency

In contrast to nuclear DNA, mtDNA cannot be studied using standard genetic engineering approaches. It is not possible yet to introduce engineered mtDNA into a functional mitochondrion. New mtDNA variants can only be introduced into cells as a part of live mitochondria, for example, by fusion with mtDNA mutant cells. Thus our knowledge is limited to naturally occurring mtDNA mutations, those that can be obtained from living carriers, i.e., for the most part, patients with inherited mitochondrial

Somatic mtDNA mutations need to be clonal to be relevant to cell physiology

While discussing phenotypic threshold in Section 3.3, we assumed (for the sake of simplicity) that mutations present in a cell were all identical. This is correct in case of inherited mtDNA mutations causing mitochondrial disease. In aging, however, mtDNA mutations are somatic, i.e., they occur at random. Thus different mtDNA molecules within a cell are expected to acquire different somatic mutations. These different mutations will most likely affect different aspects of mitochondrial genome,

Effects of Somatic mtDNA Mutations in Aging Tissues

Perhaps the weakest point of the mitochondrial mutational hypothesis of aging is the relatively low overall fraction of mtDNA mutations in aged tissues. For example, typical fraction of mtDNA deletions in aged muscle is about 1%, which may seem incompatible with any significant role in tissue physiology and thus in the aging process. To make things worse for the hypothesis, the mouse models that contain higher fractions of mtDNA deletions,45 or point mutations4 do not display any of the

Evolutionary Considerations and Interspecies Comparisons

Mutational and biochemical analysis of aging tissues described in the preceding text draws a provocative picture of substantially detrimental effects of somatic mitochondrial mutations. Yet, the evidence is not sufficient to conclude whether mtDNA mutations are significant for the aging process. Additional insight into the problem has been gained from evolutionary studies and interspecies comparison.

Acknowledgments

The authors are indebted to David Samuels, Konstantin Popadin, and Laura Greaves for their valuable discussions and Catherine MacLean and SaiSai Tao for their critical comments and Evan Feldman for help with data analysis. K. K. was supported by the Ellison Medical Foundation. D. T. was supported by Newcastle University Centre for Ageing and Vitality (supported by the BBSRC and MRC [G0700718]), The Wellcome Trust Centre for Mitochondrial Research [G906919], and UK NIHR Biomedical Research

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      But in humans and other mammals, discovering DNA polymorphisms (also known as chromosomal loci or gene variants) responsible for differences in lifespan has resisted standard mapping methods [early work reviewed by 28,33–34]. One pessimistic view has been that aging is a consequence of nearly random and irremediable process of stochastic decay driven by somatic mutations in both nuclear and mitochondrial genomes [35]. A more optimistic alternative is that differences in aging rates within species are modulated by genetic variants linked to metabolic states, accuracy of DNA repair, protein processing efficiencies, immune surveillance, and life history—what we and others call the deep causes of aging.

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