2. MITOCHONDRIAL BIOENERGETICS AND REACTIVE OXYGEN SPECIES IN DEGENERATIVE DISEASES AND AGEING
Over the past 10 years there has been a rapid rise in evidence supporting the hypothesis that mitochondrial decline is an important factor in aging. This evidence includes the demonstration that mutations in mitochondrial genes result in degenerative diseases of the central nervous system (CNS), heart, skeletal muscle, kidney, and endocrine system; that the clinical manifestations of these diseases are common complaints of the elderly; that the mitochondria produce much of the cellular energy and are also the primary source of endogenous oxygen radicals, both of which have been associated with aging; and that postmitotic tissues have been found to accumulate somatic mitochondrial DNA (mtDNA) mutations with age, which correlates with an age-related decline in mitochondrial functions. The veracity of this hypothesis has been greatly enhanced over the past 3 years by the development of mouse mutants with defects in mitochondrial energy production and reactive oxygen species (ROS) detoxification.
These mutant mice exhibit many of the symptoms of degenerative disease and aging. Hence, the mitochondrial theory of aging has now matured to the extent that it can be actively pursued within the context of a manipulable experimental paradigm.
2.1. MITOCHONDRIAL BIOENERGETICS AND FREE RADICALS
The mitochondria generate most of the cellular energy via the process oxidative phosphorylation (OXPHOS), occuring within the mitochondrial inner membrane. In OXPHOS, hydrogens derived from dietary carbohydrates and fats and borne on NADH or FADH2 are oxidised by the electron transport chain (ETC), ultimately reacting with atomic oxygen (1/2 O2) to give water (H2O). During such process beside normal ions, highly toxic superoxid radicals are produced. Superoxide anion is a toxic byproduct of OXPHOS, generated by the transfer of electrons from the ETC directly to O2 to give superoxide anion (O2.-). The primary electron donors are reduced NADH dehydrogenase (Complex I) and half-reduced CoQ (ubisemiquinone) (1-6). Superoxide anion can be converted to H2O2 by the mitochondrial MnSOD or cytosolic Cu/ZnSOD, and H2O2 can be reduced to water by gtutathione peroxidase (GPx) or catalase.
However, H2O2 in the presence of transition metals, can also be converted to the highly reactive hydroxyl radical (OH•) by the Fenton reaction (1, 2, 7). O2.-, H2O2 and OH• are known as the ROS.
Superoxide anion production and H2O2 release are highest during state IV respiration and lowest during state III respiration (8-11). Moreover, inhibition of the electron transport chain with the Complex III inhibitor antimycin A stimulates oxygen radical production (4, 9, 10). Thus, defects in the OXPHOS enzyme complexes should reduce energy production and increase ROS production and toxicity (12, 13). Superoxide reacts with and inactivates the mitochondrial enzymes containing iron-sulfur - centers including aconitase, SDH and NADH dehydrogenase (14).