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Mitochondria - Relationship Of Energy Functions To Cellular And Organismic Aging

age genetic mitochondrial free decline ros

Although oxygen plays an essential role as the terminal electron acceptor during respiration, oxygen and its metabolites are potentially cytotoxic (toxic to cells). During the course of normal oxidative phosphorylation, between 1 percent to 3 percent of all oxygen reduced by mitochondria escape from the electron transport chain into the mitochondrial inner membrane and are converted into reactive oxygen species (ROS) that have the ability to oxidize macromolecules. These oxidants, produced continuously as by-products of the anaerobic metabolic process, include superoxide (0-2), hydrogen peroxide (H202), and hydroxyl radicals (HO-) and are a continuous threat to cellular macromolecules— ROS attacks result in molecular defects found in proteins, lipids, and DNA. However, the damage to the cells is balanced by the existence of cellular enzymatic defenses, which have evolved to battle reactive oxygen species. Unfortunately, these defenses are not perfect, and, cellular macromolecules can become damaged. The accumulation of damaged macromolecules is thought to contribute significantly to aging.

In 1956, Denham Harman first proposed that free radicals play a major role in the aging process by causing cumulative macromolecule damage. Harman subsequently extended his theory and proposed that mitochondria are the major players in aging, since mitochondria are the major targets of free radicals (Harman, 1981). The free-radical theory of aging has gained a lot of support. Many age-correlated genetic data implicate mitochondrial dysfunction in the process of aging. Because of their vulnerability, the mitochondrial DNA molecules are particularly affected. In contrast to nuclear DNA, which is assembled in nucleosomes and protected by histones and other proteins, mtDNA is "naked," facilitating direct ROS attacks. In addition, mtDNA is attached to the inner mitochondrial membrane, and is therefore accessible by the by-products of respiration and a primer target for damage by ROS. Yakes and Van Houten (1997) have shown that the mtDNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress.

Age-related mitochondrial bioenergetic defects have also been reported in the electron transport chain and oxidative phosphorylation. Defective electron transport chains increase the production of mitochondrial free radicals, which in turn cause a further decline in mitochondrial functions, leading ultimately to a decline of the ATP level. Since a sufficient supply of ATP is necessary for life, the accumulation of bioenergetically defective cells is a key factor in the process of aging. Furthermore, during aging the ROS-scavenging enzymes decline, which further increases both free radicals and oxidative stress within the mitochondria.

Three different kinds of studies have been used to show that mitochondrial respiratory functions decline with age. First, histochemical analysis of respiratory enzymes has revealed an age-correlated deficiency in cytochrome-c oxidase (complex IV of the respiratory chain). This was first shown by Josef Müller-Höcker (1989) using cardiomyocytes in the human heart. Cox-deficient cardiomyocytes (heart muscle cells) are regularly present in humans beginning in the sixth decade of life. The second type of study, derives from measurements of enzymatic activities of each respiratory chain complex, as shown first by Yen et al. (1989) and Trounce et al. (1989). The third kind of study involves monitoring the changes of the mitochondrial membrane potential. The development of mitochondrial fluorescent indicators and sophisticated fluorescence microscopy has enabled organellar events to be studied (Smiley et al., 1991). As explained above, the energy released during oxidation reactions in the mitochondrial respiratory chain is stored as an electrochemical gradient consisting of transmembrane electrical potential. Since maintenance of membrane potential is essential for ATP synthesis, the decline seen in mitochondrial membrane potential is a good indicator of mitochondria malfunction.

Mitochondria - Potential Role Of Dna Damage And Dna Mutations [next]

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