Review ArticleMechanisms linking mtDNA damage and aging
Introduction
Aging is a degenerative process caused by the accumulation of cellular damage that leads to cellular dysfunction, tissue and organ failure, and death. Common features of aging include reduced tissue homeostasis and regeneration, increased oxidative stress, and accelerated cellular senescence, with consequences such as decreased immunity, decreased healing, and a generally higher level of risk factors for human diseases such as cancer or neurodegenerative disorders [1].
The biology of aging and the exact mechanisms responsible for the aging process are still a matter of discussion and even though various theories can be identified, aging is most likely a multifactorial process. Even if still controversial [2], the prevailing explanation is the “free radical theory of aging,” first proposed by Harman in the 1950s [3] and reemphasized by Ames and colleagues in the 1990s [4]. According to this theory, the major determinant of life span is the accumulation of tissue damage caused by cellular reactive oxygen species (ROS), which are highly unstable molecules that react with cellular macromolecules (lipids, proteins, and nucleic acids) and impair cellular functions [2], [5]. ROS are increased in aged tissues [6] and various lines of evidence corroborate the hypothesis that a decrease in metabolic rate attenuates oxidative damage and extends life span [6], [7]. Calorie restriction, for example, is a multitarget process that increases life span by acting on various levels: it prevents DNA damage and promotes DNA repair; it increases autophagy, decreases oxidative stress, and affects mitochondrial efficiency and energy production [8].
Mitochondria are believed to have a central role in aging. They are the organelles that supply most of the energy to the cell in the form of ATP through oxidative phosphorylation (OXPHOS) conducted by the respiratory chain. Mitochondria are also involved in other tasks such as signaling, cellular differentiation, and cell death, as well as control of the cell cycle and cell growth. A drop in cellular ATP can lead to an increase in Bax, one of the first signals in the cellular apoptosis cascade, as well as impairment of ion pump function leading to membrane failure and cell death [9].
The OXPHOS chain is composed of four respiratory complexes (complexes I to IV) and ATP synthase (complex V), all located in the mitochondrial inner membrane. During aging there is a general decline in mitochondrial functions: tissues from aged animals show a decreased capacity to produce ATP, as reported in liver, heart, and skeletal muscle [10], [11]. Moreover, the gross mitochondrial morphology is altered in aged tissues of mammals [4]; the total number of mitochondria is lower in tissues of different ages, such as liver and muscle [12], [13]; and likewise mitochondrial protein levels are decreased [14].
Mitochondria contain their own genome and most of the complexes of the electron transport chain are composed of both nuclear- and mitochondrial DNA (mtDNA)-encoded proteins. Since the discovery of mtDNA diseases, and with the finding that mtDNA mutations can lead to mitochondrial dysfunctions, many efforts have been dedicated to the analysis of mtDNA changes and their role in aging.
Section snippets
Mitochondrial DNA
The human mitochondrial genome is a circular, double-stranded, supercoiled molecule present in one to several thousand copies per cell [15]. It is maternally inherited and the copy number per cell varies according to the bioenergetic needs of the tissue. It is composed of 16,569 bp and encodes 37 genes (22 tRNA molecules, 2 mitochondrial rRNAs, and 13 proteins). There are two strands, called the “H-strand” (heavy) and “L-strand” (light), which are respectively enriched in guanines and
MtDNA damage and repair mechanisms
The mtDNA mutation rate is believed to be 10 times higher than that of nDNA [21], and multiple factors have been proposed to explain this phenomenon.
First of all, mtDNA is organized in “nucleoids,” dynamic structures of mitochondrial proteins and mtDNA. Proteins involved in mtDNA transcription and replication are localized in nucleoids, as well as other proteins involved in mtDNA packaging, including Twinkle, mtSSB, and TFAM. TFAM in particular is the most abundant protein and it is important
MtDNA turnover in aging
MtDNA maintenance and mitochondrial function rely on efficient mtDNA turnover that is determined by biogenesis, dynamics, and selective autophagic removal of defective organelles. These mechanisms are essential for mtDNA stability, and their changes during the aging process may affect the mtDNA integrity [29]. There is evidence suggesting that aging is associated with decreased mtDNA copy numbers (described in detail in the next paragraphs). One possible explanation is an age-related decrease
MtDNA changes in aging
Various studies support the notion that mtDNA expression decreases with age, whereas mutations accumulate [46]. The idea that the increased rate of mutation is relevant to the aging process dates to the 1980s [47]. One of the first reports connecting mtDNA damage and aging was published in 1988, when Piko et al. reported an increased frequency of deletions in senescent rats and mice [48]. In 1990, Cortopassi et al. [49] showed how low levels of a common deletion (5 kb between nucleotides 8470
The mitochondrial free radical theory of aging
As mentioned above, the mitochondrial free radical theory of aging has been the most accredited theory after its first postulation. Because it has been analyzed in detail in numerous reviews [66], [67], [68], [69], we will only briefly analyze the main characteristics and controversies. Mitochondria are an important source of ROS, in particular of superoxide anion, which is formed at complexes I and III [70], [71] of the electron transport chain in the mitochondrial inner membrane. Metabolic
The clonal expansion theory
Other than the theory of the vicious cycle intrinsic to the mitochondrial free radical theory of aging, another possibility is that mtDNA mutations accumulate mostly by clonal expansion. According to this hypothesis, in some cells that carry the initial mutation, there occurs clonal expansion so that the threshold of mutated mtDNA reaches a pathogenic level with age, affecting over time the whole tissue [92]. In other words, inherited or de novo mutated mtDNA undergoes clonal expansion until
An alternative role for ROS
From the most recent work, it is more apparent how the classical mitochondrial free radical theory of aging must be revisited [75]. Even though it is clear how mtDNA damage and ROS do have a role in the aging process, their correlation is still extensively under investigation. One hypothesis is that the increase in ROS is a consequence rather than a cause of aging [69] and that the role of ROS is to mediate the stress response to age-dependent damage.
ROS are not purely detrimental reactive
From mtDNA damage to tissue failure
The discovery of mitochondrial diseases was the first proof that mutations in mtDNA lead to mitochondrial dysfunction [120]. However, in aging, how an mtDNA mutation can finally lead to tissue failure is not yet completely clarified.
As previously mentioned, mutations have to reach a pathogenic threshold to have an effect on mitochondrial function [64], and the mutations accumulated in aged tissues are significant but still very low compared, for example, to mitochondrial diseases. A recent
Conclusions
Since the discovery of a link between mtDNA mutations, mitochondrial dysfunction, and mitochondrial diseases, great efforts have been made to investigate the role of mtDNA mutations in aging. The accumulation of mtDNA deletions and point mutations, together with the increase in ROS in aging tissues, led naturally to the mitochondrial free radical theory of aging. If at the beginning this original theory was very appealing owing to numerous examples of indirect evidence linking mtDNA, ROS,
Acknowledgments
Our work is supported by the U.S. National Institutes of Health, Grants 5R01EY010804, 1R01AG036871, 1R01NS079965, and 1R21ES025673; the Muscular Dystrophy Association; the United Mitochondrial Disease Foundation; and the JM Fund for Mitochondrial Disease Research.
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