Inhibition of mitochondrial respiratory chain complex 1 protects neuronal cells from oxidative stress-induced necrotic cell death = 미토콘드리아 전자전달계 복합체 1 억제의 산화성 스트레스에 대한 신경세포 보호 효과

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Oxidative stress is deeply involved in various neuronal diseases including neurodegenerative diseases, stroke and ischemia/reperfusion injury. I observed that $H_2O_2$ induced poly(ADP-ribose) polymerase (PARP)-dependent necrotic cell death which was prevented by diphenyleneiodonium (DPI) pretreatment. It was shown that DPI prevented the cell death by inhibiting mitochondrial respiratory chain complex I among various flavoproteins that can be inhibited by DPI, as a specific inhibitor of mitochondrial complex I, rotenone, prevented $H_2O_2$-induced cell death. In search of the preventive effects of inhibitors of mitochondrial complex I, I detected mitochondrial hyperpolarization and subsequent intracellular generation of reactive oxygen species (ROS) triggered by exogenous $H_2O_2$. DPI and rotenone inhibit both. $H_2O_2$ also induced c-Jun N-terminal kinase (JNK) phosphorylation in biphasic pattern, of which only the second peak was inhibited by DPI pretreatment. JNK inhibitor blocked mitochondrial hyperpolarization and intracellular ROS generation, whereas PARP inhibitor did not block mitochondrial hyperpolarization. In vivo study of middle cerebral artery occlusion model implied protective effect of DPI and rotenone in ischemia/reperfusion injury. In summary, I suggest that when oxidative stress is given, JNK phosphorylation, mitochondrial hyperpolarization and intracellular ROS generation form a vicious cycle, leading to PARP over-activation and eventually to cell death. Inhibition of mitochondrial complex I could break the vicious cycle and prevent oxidative stress-induced cell death, and it had a potential capability of therapeutic interventions in oxidative stress-induced neuronal diseases.
Advisors
Choi, Chul-Heeresearcher최철희researcher
Description
한국과학기술원 : 바이오및뇌공학과,
Publisher
한국과학기술원
Issue Date
2008
Identifier
310635/325007  / 020063127
Language
eng
Description

학위논문(석사) - 한국과학기술원 : 바이오및뇌공학과, 2008.2, [ iv, 39 p. ]

Keywords

mitochondria; neuron; oxidative stress; cell death; 미토콘드리아; 뇌세포; 산화성 스트레스; 세포 괴사; mitochondria; neuron; oxidative stress; cell death; 미토콘드리아; 뇌세포; 산화성 스트레스; 세포 괴사

URI
http://hdl.handle.net/10203/27176
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=310635&flag=dissertation
Appears in Collection
BiS-Theses_Master(석사논문)
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