Effects of Brain Mitochondrial Metabolism, Aging, and Caloric Restriction on Membrane Lipids and Proteins

Abstract

Recent evidence has shown that an inevitable consequence of living in an aerobic environment is the continuous production of oxygen free radicals. The major organelle responsible for this generation of endogenous free radicals is the mitochondrion. Apart from its nurturing role including ATP synthesis in a cell, the mitochondrion is accountable for the most oxidants produced by cells during normal aerobic respiration. This makes intuitive sense considering that mitochondria consume greater than 80% of the available oxygen in the cellular milieu. The free radical theory of aging, as proposed by Harman (1), postulates that oxygen-derived free radicals result in a cumulative damage to critical cellular components, eventually leading to many age-related disorders. An increase in the metabolic rate could lead to a substantial production of endogenous oxidants, such as superoxide (O₂ ^−·), hydrogen peroxide (H₂O₂), hydroxyl radical (OH^·), as by-products of normal oxygen metabolism in the mitochondria. Studies corroborating this suggestion have demonstrated that consequent damage in terms of the level of oxidative DNA damage is roughly related to metabolic rate in a number of mammalian species (1–3). Apart from normal brain aging, it is hypothesized that there is a free radical mediated deterioration of neuronal membrane components leading to age-related neurodegenerative disorders such as Alzheimer’s disease, Parkinsonism, amyotrophic lateral sclerosis, and Huntington’s disease. Harman was the first to propose that the mitochondrion was involved in the aging process (4). The dysfunctional mitochondrion is a cellular organelle that also has been implicated in several neurodegenerative disease states (5). Evidence suggests that biomolecular components of the mitochondria, such as mitochondrial DNA (mtDNA), electron transport chain enzymes (e.g., cytochrome oxidase), and lipid components (e.g., cardiolipin) undergo possible free radical mediated deterioration, resulting in a compromise of the associated bioenergetic processes (4–5). The tightly coupled process of oxidative phosphorylation during mitochondrial respiration utilizes the electron transport chain to accomplish a four-electron reduction of O₂ to water with a simultaneous production of ATP through phosphorylation of ADP. A temporary or sustained loss of mitochondrial function and ATP production has been implicated in etiology of several neurodegenerative disorders (5,6).