Mitochondrial DNA damage and animal longevity: insights from comparative studies

Abstract

Chemical reactions in living cells are under strict enzyme control and conform to a tightly regulated metabolic program. However, uncontrolled and potentially deleterious endogenous reactions occur, even under physiological conditions. Aging, in this chemical context, could be viewed as an entropic process, the result of chemical side reactions that chronically and cumulatively degrade the function of biological systems. Mitochondria are a main source of reactive oxygen species (ROS) and chemical sidereactions in healthy aerobic tissues and are the only known extranuclear cellular organelles in animal cells that contain their own DNA (mtDNA). ROS can modify mtDNA directly at the sugar-phosphate backbone or at the bases, producing many different oxidatively modified purines and pyrimidines, as well as single and double strand breaks and DNA mutations. In this scenario, natural selection tends to decrease the mitochondrial ROS generation, the oxidative damage to mtDNA, and the mitochondrial mutation rate in long-lived species, in agreement with the mitochondrial oxidative stress theory of aging.

Figure 1

Schematic diagram of mitochondrial processes that are important for aging and longevity. The schematic shows that mitochondrial complex I is the main ROS generator. Several physiological mechanisms influencing the rate of mitochondrial ROS generation include: (i) the relative concentration of the respiratory complexes, (ii) the degree of electronic reduction of these generators, (iii) the uncoupling proteins, and (iv) specific chemical modifications. Oxygen radicals attack lipids, carbohydrates, proteins, and DNA. The products of lipid peroxidation include highly reactive molecules that can also cause lipoxidative damage to mitochondrial DNA. The scheme highlights two main characteristics of long-lived animal species likely contributing to their slow aging rate and superior longevity: highly resistant macromolecular components and low rate of generation of endogenous damage. Abbreviations: 8-oxodG, 8-oxo-7,8-dihydro-2′-deoxyguanosine; M1dG, Malondialdehyde-deoxyguanosine; HNE-dG, 4-hydroxy-2-nonenal-deoxyguanosine; HOPdG, Acrolein-deoxyguanosine.