Hibernation during Hypoxia in Cardiomyocytes

Abstract

During myocardial hibernation, decreases in coronary perfusion elicit inhibition of contraction, suggesting that energy demand is attenuated. We previously found an inhibition of contraction and O consumption during hypoxia (3% O; O = 20 torr for >2 h) in cardiomyocytes, which was reversible after reoxygenation. This study sought to determine whether mitochondria function as cellular O sensors mediating this response. Embryonic cardiomyocytes were studied under controlled O conditions. Hypoxia produced no acute decrease in mitochondrial potential as assessed using tetramethylrhodamine ethylester (TMRE). Cellular [ATP] was preserved throughout hypoxia, as assessed using the probe Magnesium Green. Thus, ATP synthesis and utilization remained closely coupled. Cells adapted to hypoxia for >2 h exhibited a 4% increase in mitochondrial potential upon reoxygenation, suggesting that a partial inhibition of cytochrome oxidase had existed. To test whether the oxidase serves as an Osensor, azide was administered (1 m) to simulate the effects of hypoxia by lowering the of the oxidase. The effects of azide on contraction and mitochondrial potential mimicked the response to hypoxia. We conclude that partial inhibition of cytochrome oxidase during hypoxia allows mitochondria to function as the O sensor mediating the decreases in ATP utilization and O consumption during hypoxia.