MITOCHONDRIAL GLUTATHIONE OXIDATION CORRELATES WITH AGE-ASSOCIATED OXIDATIVE DAMAGE TO MITOCHONDRIAL-DNA

Mitochondria may be primary targets of free radical damage associated with aging. We have found that mitochondrial glutathione is markedly o xidized with aging in rats and mice. The oxidized to reduced glutathio ne ratio rises with aging in the liver, kidney, and brain. The magnitu de of these changes is much higher than that previously found in whole cells of any species previously studied. In the liver, this ratio (ex pressing GSSG as a percent of GSH) changed from 0.77 +/- 0.19% (n=5) i n young rats to 2.47 +/- 1.25% (n=5) in old ones, i.e., 320% of the co ntrols. In the brain and kidney, values for old rats were, respectivel y, 600 and 540% higher than those of young rats. A marked oxidation of mitochondrial glutathione also occurred in mice. Aging also caused an increase in 8-oxo-7,8-dihydro-2'-dexoyguanosine levels in mtDNA in ra ts and mice. Oral antioxidant administration protected against both gl utathione oxidation and mtDNA damage in rats and mice. Finally, we hav e found a direct relationship between mtDNA damage and mitochondrial g lutathione oxidation. This occurs both in rats (r=0.95) and in mice (r =0.98). This relationship, which has been observed for the first time in these studies, underscores the role of glutathione in the protectio n against free radical damage that occurs upon aging.