The free radical theory of aging, originally proposed in 1956, hypothesizes that aging is a result of an accumulation of oxidative damage to macromolecules by free radicals produced during normal metabolism (1). Mitochondria are the major source of reactive oxygen species (ROS) within the cell and are essential for maintaining cellular homeostasis. Therefore, it has been proposed that a loss of mito-chondrial function with age potentially contributes to the degenerative processes of aging. Mitochondria contain their own genome that typically encodes 13 proteins of the respiratory chain, as well as their own ribosomal RNAs and tRNAs. The exact number of proteins encoded by the mitochondrial DNA (mtDNA) varies among species. mtDNA is in close proximity to the site of production of ROS, and therefore, it has been hypothesized that mtDNA unusually will be prone to an accumulation of oxidative damage, and consequently might accumulate potentially deleterious mutations during aging. It is speculated that these mutations in turn may lead to many of the degenerative changes associated with aging. This theory was originally proposed by Miguel in 1980 and further elaborated on by others (2-6).

Each mitochondrion within the cell contains multiple copies of the mito-chondrial genome. MtDNA encodes genes for proteins that are required for the production of adenosine triphosphate (ATP) through oxidative phosphorylation (Fig. 1). There are four holoenzyme complexes that facilitate the transfer of electrons from reducing equivalents to water during oxidative phosphorylation. Complex I (NADH-UQ oxidoreductase) is the largest of these complexes, containing

at least 43 subunits (7,8), although the final structure has yet to be determined. Complex II (succinate dehydrogenase) is entirely nuclear encoded and is composed of 4 subunits (9), complex III (ubiquinone-cytochrome c oxidoreductase) is composed of 11 subunits, only 1 of which is mitochondrial encoded (10), and complex IV (cytochrome c oxidase) has 3 mitochondrial encoded subunits and 10 nuclear encoded subunits (11). Oxygen radicals produced as a by-product of normal respiration can theoretically damage mtDNA, perhaps resulting in a reduction of necessary components of the oxidative phosphorylation machinery and thus a reduction in the amount of net ATP produced. This theory, espoused over the last decade by numerous investigators, states that this creates a "vicious cycle," whereby increased oxidative stress arising from mtDNA mutations engenders more mtDNA mutations, which further impairs mitochondrial function and eventually results in many of the degenerative changes of aging (6,12,13). It is clear that this hypothesis is intellectually appealing, primarily because mitochondria occupy an undisputed central role in maintaining cellular homeostasis, and eu-karyotes have an absolute requirement for optimal mitochondrial function in order to survive. Although this theory is intellectually attractive, careful review -

Figure 1 Mitochondrial Production of the Reactive Oxygen Species. This figure has been simplified for clarity. A Roman numeral represents each respiratory chain complex, and mtDNA is depicted in its supercoiled form attached to the inner membrane. O2 = superoxide, Q = ubiquinone, Q = ubisemiquinone, GpX = glutathione peroxidase. For a full description of the process of oxidative phosphorylation, see Ref. 10. Briefly, reducing equivalents such as NADH or succinate donate electrons at either complex I or II. Sequential electron transfers take place using redox components of each of the complexes of the respiratory chain (complexes I-IV), which ultimately lead to the reduction of oxygen to water concomitant with the production of ATP at the ATP synthase (not shown) through utilization a chemiosmotic proton circuit. Each of these complexes is composed of nuclear and mitochondrially encoded subunits with the exception of complex II. Complex I (NADH-UQ oxidoreductase), the largest respiratory complex (at least 43 subunits) is also believed to be a major site of production of superoxide (Ref. 93). Complex II (succinate dehydrogenase) contains four subunits as well as a cytochrome b of unknown function. Mutations in this cytochrome in C. elegans cause increased oxidative stress and a shortened life span (Refs. 60, 61, 65). Complex III (ubiquinone-cytochrome c oxidoreductase) is composed of 11 subunits and also is believed to be a site of ROS production within the mitochondria (Ref. 94). Complex IV (cytochrome c oxidase) is composed of 13 subunits. Ubiquinone (Q) is a major electron carrier within the respiratory chain and is present at high levels within the inner mitochondrial membrane (Ref. 95). When reduced, it forms ubiquinol (Q), which can donate electrons to oxygen present within the mitochondria. This forms superoxide, which can be detoxified by SOD2 in the matrix to yield hydrogen peroxide, which is free to diffuse out of the mitochondria owing to its uncharged nature. Recent data indicate that SOD1 is present in the intermembrane space (V. Culotta, personal communication), indicating that superoxide must exist in this location as well.

demonstrates that although there are some intriguing correlations with aging for the incidence of mitochondrial DNA mutations, there is little evidence for a central role in the aging process (14). Perhaps the best test for evaluating this hypothesis is an animal model with high levels of mtDNA mutations and an examination of tissues from this animal for evidence of oxidative stress. Such a model has recently been reported (15,16), and we will summarize their findings later in this chapter.

Mitochondrial proteins, lipids, and DNA are all targets of oxidative stress, and damage to any one of these components could result in an increase in damage to other constituents of the mitochondria. Research into the role of oxidative modifications to these three components of the mitochondria in aging has been the focus of research in many laboratories (for a comprehensive review of this topic, see Ref. 17). This chapter will review current data concerning the potential targets of oxidative damage within mitochondria in animal models, endogenous and exogenous defenses against endogenously produced reactive oxygen species, and the role that this oxidative damage may play in aging.

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