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Role of Mitochondria in oxidative stress and the aging process
I p-5 I PROTEIN
OXIDATION
&&&&mu. Laboratory Institute, Bethesdn, Marylnnd
IN AGING AND DISEASE
ofBiochemistry, National USA.
Heart, Lung, and Blood
Older humans and animals look rather different than younger ones, implying that there must be an age-related change in cellular proteins. Age-dependent changes in the steady-state levels of particular proteins are well-documented, often being considered part of the continuum of developmental biology. However, proteins may also exhibit changes in their function, including alteration of receptors, enzymes, and structural proteins. A change in function requires a change in shape, or conformation. Proteins can switch between specific conformations, each exhibiting different properties. Conformational switches can be induced through a variety of mechanisms, including the binding of small molecules or simply a change in pH. Covalent modifications also induce conformational changes, sometimes irreversibly. A large body of published evidence has now established that oxidative modifications of proteins occur during aging and in a variety of pathophysiologic conditions, many being neurodegenerative diseases including Alzheimer’s disease. These covalent modifications include peptide bond cleavage, glycoxidation, lipoxidation, sulfoxidation, nitration, chlorination, hydroxylation, and especially carbonylation of amino acids in proteins. During the last third of lifespan, the average cellular content of protein carbonyl increases markedly from basal levels, often reaching the point where one of every three protein molecules carries a carbonyl group. At this level, these dysfunctional molecules are likely to deleteriously affect most aspects of cellular function. (This presentation is part of The Dorothy Dillon Eweson Series on Advances in Aging Research, supported by the American Federation for Aging Research.)
Role of Mitochondriu in Oxidutive Stress and the Aging Process R.S. Sohal, Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275 Several lines of evidence support the idea that mitochondria play a crucial role in the aging process. The rates of mitochondrial0; and H,O, generation are elevated with age in mammalian tissues and in insects. Simultaneously, oxidative damage to mitochondria and other cellular components increases with age, and is hypothesized to be a major contributory factor in physiological attrition associated with senescence. Experimental evidence supports the idea that accrual of oxidative damage to mitochondria is a causal factor in the age-associated increase in mitochondrial 0,-&&O, generation. Experimental regimens, which increase life span, such as caloric restriction in rodents and hypometabolic states in cold-blooded animals cause a decrease in the rate of mitochondrial OZ./f-&O, generation. Rates of mitochondrial O;/HZOZ generation are inversely correlated with maximum life spans in mammalian and insect species. Recent studies have indicated that oxidative damage to mitochondrial proteins during aging is a highly selective rather than a random phenomenon. In the flight muscle mitochondria of the housefly, only adenine nucleotide translocase and aconitase exhibit a notable increase in protein oxidative damage, indicated by carbonylation accompanied by a decline in functional activity. The ratios of the activities of mitochondrial respiratory complexes are also altered during aging, facilitating decreases in respiratory efficiency and increased autoxidizability of electron carriers.
54
OXYGEN
f
9
9
OXIDATION
&&&&mu. Laboratory Institute, Bethesdn, Marylnnd
IN AGING AND DISEASE
ofBiochemistry, National USA.
Heart, Lung, and Blood
Older humans and animals look rather different than younger ones, implying that there must be an age-related change in cellular proteins. Age-dependent changes in the steady-state levels of particular proteins are well-documented, often being considered part of the continuum of developmental biology. However, proteins may also exhibit changes in their function, including alteration of receptors, enzymes, and structural proteins. A change in function requires a change in shape, or conformation. Proteins can switch between specific conformations, each exhibiting different properties. Conformational switches can be induced through a variety of mechanisms, including the binding of small molecules or simply a change in pH. Covalent modifications also induce conformational changes, sometimes irreversibly. A large body of published evidence has now established that oxidative modifications of proteins occur during aging and in a variety of pathophysiologic conditions, many being neurodegenerative diseases including Alzheimer’s disease. These covalent modifications include peptide bond cleavage, glycoxidation, lipoxidation, sulfoxidation, nitration, chlorination, hydroxylation, and especially carbonylation of amino acids in proteins. During the last third of lifespan, the average cellular content of protein carbonyl increases markedly from basal levels, often reaching the point where one of every three protein molecules carries a carbonyl group. At this level, these dysfunctional molecules are likely to deleteriously affect most aspects of cellular function. (This presentation is part of The Dorothy Dillon Eweson Series on Advances in Aging Research, supported by the American Federation for Aging Research.)
Role of Mitochondriu in Oxidutive Stress and the Aging Process R.S. Sohal, Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275 Several lines of evidence support the idea that mitochondria play a crucial role in the aging process. The rates of mitochondrial0; and H,O, generation are elevated with age in mammalian tissues and in insects. Simultaneously, oxidative damage to mitochondria and other cellular components increases with age, and is hypothesized to be a major contributory factor in physiological attrition associated with senescence. Experimental evidence supports the idea that accrual of oxidative damage to mitochondria is a causal factor in the age-associated increase in mitochondrial 0,-&&O, generation. Experimental regimens, which increase life span, such as caloric restriction in rodents and hypometabolic states in cold-blooded animals cause a decrease in the rate of mitochondrial OZ./f-&O, generation. Rates of mitochondrial O;/HZOZ generation are inversely correlated with maximum life spans in mammalian and insect species. Recent studies have indicated that oxidative damage to mitochondrial proteins during aging is a highly selective rather than a random phenomenon. In the flight muscle mitochondria of the housefly, only adenine nucleotide translocase and aconitase exhibit a notable increase in protein oxidative damage, indicated by carbonylation accompanied by a decline in functional activity. The ratios of the activities of mitochondrial respiratory complexes are also altered during aging, facilitating decreases in respiratory efficiency and increased autoxidizability of electron carriers.
54
OXYGEN
f
9
9