Aging: A mitochondrial DNA perspective, critical analysis and an update

Abstract

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 achievable levels of mtDNA damage. New evidence suggests that both experimentally induced oxidative stress and radiation therapy result in very low levels of mtDNA mutagenesis. Recent advances provide evidence against the existence of the "vicious" cycle of mtDNA damage and ROS production. Meta-studies reveal no longevity benefit of increased antioxidant defenses. Simultaneously, exciting new observations from both comparative biology and experimental systems indicate that increased ROS production and oxidative damage to cellular macromolecules, including mtDNA, can be associated with extended longevity. A novel paradigm suggests that increased ROS production in aging may be the result of adaptive signaling rather than a detrimental byproduct of normal respiration that drives aging. Here, we review issues pertaining to the role of mtDNA in aging.

Keywords: Aging; Antioxidants; DNA damage; DNA repair; Electron transport; Mitochondrial DNA; Mitochondrial DNA degradation; Reactive oxygen species; Reactive oxygen species signaling; Somatic mtDNA mutations.

Figure 1

“Vicious cycle” of reactive oxygen species production, mitochondrial DNA damage, mitochondrial DNA mutagenesis and further reactive oxygen species production. The cycle implies an exponential growth of reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) mutagenesis.

Figure 2

The map of human mitochondrial DNA. OH and OL: Origins of heavy and light strand replication, respectively; ND1-ND6: Subunits of NADH dehydrogenase (ETC complex I) subunits 1 through 6; COX1-COX3: Subunits of cytochrome oxidase subunits 1 through 3 (ETC complex IV); ATP6 and ATP8: Subunits 6 and 8 of mitochondrial ATPase (complex V); Cyt b: Cytochrome b (complex III); ETC: Electron transport chain.

Figure 3

Consequences of unrepaired DNA damage in the nucleus and in the mitochondria. Oxidative damage induces lesions in both nDNA (left) and mtDNA (right). Both nuclei and mitochondria possess DNA repair systems to deal with these lesions. However, cellular consequences of unrepaired damage to nDNA and mtDNA are different. While persistent damage in nDNA results in the activation of cell cycle checkpoints, growth arrest, senescence and death. In contrast, mtDNA molecules with unrepairable damage are simply degraded and new molecules are synthesized using intact molecules as templates. This figure uses Servier elements available under Creative Commons license (155).