Oxidative stress-induced necrotic cell death via mitochondira-dependent burst of reactive oxygen species.
Oxidative stress is deeply involved in various brain diseases, including neurodegenerative diseases, stroke, and ischemia/reperfusion injury. Mitochondria are thought to be the target and source of oxidative stress. We investigated the role of mitochondria in oxidative stress-induced necrotic neuronal cell death in a neuroblastoma cell line and a mouse model of middle cerebral artery occlusion. The exogenous administration of hydrogen peroxide was used to study the role of oxidative stress on neuronal cell survival and mitochondrial function in vitro. Hydrogen peroxide induced non-apoptotic neuronal cell death in a c-Jun N-terminal kinase- and poly(ADP-ribosyl) polymerase-dependent manner. Unexpectedly, hydrogen peroxide treatment induced transient hyperpolarization of the mitochondrial membrane potential and a subsequent delayed burst of endogenous reactive oxygen species (ROS). The inhibition of mitochondrial hyperpolarization by diphenylene iodonium or rotenone, potent inhibitors of mitochondrial respiratory chain complex I, resulted in reduced ROS production and subsequent neuronal cell death in vitro and in vivo. The inhibition of mitochondrial hyperpolarization can protect neuronal cells from oxidative stress-induced necrotic cell death, suggesting a novel method of therapeutic intervention in oxidative stress-induced neurological disease.
Choi
Kyungsun
K
Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
Kim
Jinho
J
Kim
Gyung W
GW
Choi
Chulhee
C
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D006861:Hydrogen Peroxide / Q000633:toxicity; D007202:Indicators and Reagents; D002546:Ischemic Attack, Transient / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009336:Necrosis; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology; D016897:Respiratory Burst / Q000502:physiology*; D014475:Uncoupling Agents / Q000494:pharmacology
D007202:Indicators and Reagents; D016877:Oxidants; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; D048670:MAP Kinase Kinase 4