CARDIAC REPERFUSION INJURY - AGING, LIPID-PEROXIDATION, AND MITOCHONDRIAL DYSFUNCTION

Cardiac reperfusion and aging are associated with increased rates of m itochondrial free radical production, Mitochondria are therefore a lik ely site of reperfusion-induced oxidative damage, the severity of whic h may increase with age, 4-Hydroxy-2-nonenal (HNE), a major product of lipid peroxidation, increases in concentration upon reperfusion of is chemic cardiac tissue, can react with and inactivate enzymes, and inhi bits mitochondrial respiration in vitro. HNE modification of mitochond rial protein(s) might, therefore, be expected to occur during reperfus ion and result in: loss in mitochondrial function, In addition, this p rocess may be more prevalent in aged animals, To begin to test this hy pothesis, hearts from 8- and 24-month-old rats were perfused in Langen dorff fashion and subjected to periods of ischemia and/or reperfusion, The rate of state 3 respiration of mitochondria isolated from hearts exposed to ischemia (25 min) was approximately 25% less than that of c ontrols, independent of age, Reperfusion (40 min) caused a further dec line in the rate of state 3 respiration in hearts isolated from 24- bu t not 8-month-old rats. Furthermore, HNE modification of mitochondrial protein (similar to 30 and 44 kDa occurred only during reperfusion of hearts from 24-month-old rats, Thus, HNE-modified protein was present in only those mitochondria exhibiting reperfusion-induced declines in function, These studies therefore identify mitochondria as a subcellu lar target of reperfusion damage and a site of age-related increases i n susceptibility to injury.