Involvement of JNK-Dependent Mitochondrial Respiratory Burst in Oxidative Stress- induced Neurinal Cell Death

다국어 초록 (Multilingual Abstract)

Reactive oxygen species(ROS), especially hydrogen peroxide(H₂O₂) and superoxide anion, exert detrimental effects on cell survival and are known to be involved in a variety of pathophysiologic conditions. In this study, we demonstrate that exogenous H₂O₂ exerts cytotoxic effects via a late-phase surge of endogenous ROS(mainly superoxide anion) generated by activated mitochondria. Such delayed generation of ROS was suppressed by diphenylene iodonium or rotenone, potent inhibitors of mitochondrial respiratory chain complex Ⅰ. Secondary production of ROS was preceded by a transient hyperpolarization of the mitochondrial transmembrane potential(ΔΨm), which was accompanied by increased production of ATP. Delayed production of superoxide anion was also observed in the reperfused ischemic brains, and blockage of mitochondrial hyperactivation by rotenone reduced ROS production and the infarction volumes. Sustained activation of c-Jun N-terminal kinase(JNK) has been known to mediate oxidative stress-induced neuronal cell death in ischemic-reperfusion injury. We further demonstrate here that the JNK pathway is responsible for the mitochondrial hyperactivation, which results in delayed ROS generation and subsequent neuronal cell death in vitro and in vivo.