COMPLEX III AUGMENTS OXIDANTS DAMAGE IN ISCHEMIC AGED HEART

老年心脏缺血再灌注后心肌损伤加重。与成年对照6个月相比，衰老降低了24个月Fischer 344大鼠心脏的氧化磷酸化速率和电子传递链HI和IV复合物的活性。衰老损伤对心肌线粒体纤维间细胞群具有选择性。

Myocardial injury is increased following ischemia and reperfusion in the aged heart. Aging decreases the rate of oxidative phosphorylation and the activity of complexes HI and IV of the electron transport chain in the 24 mo. Fischer 344 rat heart, compared to 6 mo. adult controls. The aging impairment is selective to the interfibrillar population of cardiac mitochondria 0FM) that reside among the myofibrils, whereas subsarcolemmal mitochondria (SSM), located beneath the plasma membrane, are unaltered. Complex III contains 11 peptide subunits, including three catalytic centers: cytochrome b, cytochrome c1, and the Rieske iron-sulfur protein (ISP). Aging modifies cytochrome b at the site of substrate oxidation, the Qo site, in IFM. The aging defect in complex III in IFM leads to an increased production of reactive oxygen species (ROS) in the baseline state. Mitochondrial damage occurs during ischemia in the adult and aged heart. Ischemia damages the ISP of complex III and decreases complex III activity in both populations of mitochondria in adult and aged hearts. In contrast to the adult heart, the aged heart sustains additional oxidative damage to both SSM and IFM during ischemia. Cardiolipin, a key inner mitochondrial membrane phospholipid, is modified only in the aged heart, generating a new molecular species of cardiolipin. Cytochrome c, located in proximity to cardiolipin, is modified, again, only in the aged heart. Cytochrome oxidase activity decreases following ischemia in the aged heart, and, unlike in the adult heart, activity cannot be restored following the addition of exogenous phospholipid. This observation in the aged heart indicates that ischemia led to persistent damage to a peptide subunit of cytochrome oxidase, rather than reversible damage to the inner membrane environment of the complex as in the adult heart. Thus, during ischemia, specific molecular targets in the electron transport chain, including cardiolipin, sustain oxidative damage only in the aged heart. Mitochondria are the major source of the ROS generated during myocardial ischemia. Complex III is the major site of ROS production within mitochondria in the adult heart The role of complex III in the oxidative damage sustained by the aged heart during ischemia is unknown. We found that limitation of electron flow into complex III during ischemia achieved by blockade of complex I with rotenone immediately prior to ischemia preserves the rate of oxidative phosphorylation through complexes III and IV in the aged heart. We propose that during ischemia complex III is a key mechanism of the enhanced oxidative damage observed in the aged heart, We hypothesize that ROS from complex III damage cytochrome oxidase in the aged heart. Oxidative damage during ischemia is accelerated in IFM by the aging defect present at Qo site of complex III. We hypothesize that damage to cytochrome oxidase leads in turn to oxidative modification of cytochrome c and cardiolipin. We hypothesize that following ischemic damage to aged heart mitochondria, ROS production and release is increased, setting the stage for oxidative damage during reperfusion. Enhanced ROS release from mitochondria, in turn, amplifies cardiac damage and dysfunction during reperfusion that can be decreased by reversibly limiting electron flow into complex III during ischemia.