Mitochondrial phospholipase A2 activated by reactive oxygen species in heart mitochondria induces mild uncoupling

Homeostasis of reactive oxygen species (ROS) in cardiomyocytesis critical for elucidation of normal heart physiology andpathology. Mitochondrial phospholipases A2 (mt-PLA2) have beenpreviously suggested to be activated by ROS. Therefore, we haveattempted to elucidate physiological role of such activation. Wehave found that function of a specific i-isoform of mitochondrialphospholipase A2 (mt-iPLA2) is activated by tert-butylhydroperoxide in isolated rat heart mitochondria. Isoform specificitywas judged from the inhibition by bromoenol lactone (BEL), aspecific iPLA2 inhibitor. Concomitant uncoupling has been causedby free fatty acids, since it was inhibited by bovine serumalbumin. The uncoupling was manifested as a respiration burstaccompanied by a slight decrease in mitochondrial innermembrane potential. Since this uncoupling was sensitive tocarboxyatractyloside and purine nucleotide di- and triphosphates, we conclude that it originated from the onset offatty acid cycling mediated by the adenine nucleotide translocase(major contribution) and mitochondrial uncoupling protein(s)(minor contribution), respectively. Such a mild uncoupling mayprovide a feedback downregulation of oxidative stress, since itcan further attenuate mitochondrial production of ROS. Inconclusion, ROS-induced function of cardiac mt-iPLA2 may standon a pro-survival side of ischemia-reperfusion injury.