Oxidative damage during aging targets mitochondrial aconitase.
The mechanisms that cause aging are not well understood. The oxidative stress hypothesis proposes that the changes associated with aging are a consequence of random oxidative damage to biomolecules. We hypothesized that oxidation of specific proteins is critical in controlling the rate of the aging process. Utilizing an immunochemical probe for oxidatively modified proteins, we show that mitochondrial aconitase, an enzyme in the citric acid cycle, is a specific target during aging of the housefly. The oxidative damage detected immunochemically was paralleled by a loss of catalytic activity of aconitase, an enzyme activity that is critical in energy metabolism. Experimental manipulations which decrease aconitase activity should therefore cause a decrease in life-span. This expected decrease was observed when flies were exposed to hyperoxia, which oxidizes aconitase, and when they were given fluoroacetate, an inhibitor of aconitase. The identification of a specific target of oxidative damage during aging allows for the assessment of the physiological age of a specific individual and provides a method for the evaluation of treatments designed to affect the aging process.
Yan
L J
LJ
Department of Biological Sciences, Southern Methodist University, Dallas, TX 75275, USA.
Levine
R L
RL
Sohal
R S
RS
D000154:Aconitate Hydratase / Q000737:chemistry / Q000378:metabolism*; D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology; D002417:Cattle; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005463:Fluoroacetates / Q000494:pharmacology; D006793:Houseflies / Q000201:enzymology / Q000254:growth & development*; D007700:Kinetics; D008136:Longevity; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D008929:Mitochondria, Heart / Q000201:enzymology; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D010100:Oxygen / Q000494:pharmacology; D016415:Sequence Alignment
D004791:Enzyme Inhibitors; D005463:Fluoroacetates; D000154:Aconitate Hydratase; D010100:Oxygen