title: Roles of PTEN-induced putative kinase 1 and dynamin-related protein 1 in transient global ischemia-induced hippocampal neuronal injury.
abstract: Recent studies showed that increased mitochondrial fission is an early event of cell death during cerebral ischemia and dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission, which may be regulated by PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase thought to protect cells from stress-induced mitochondrial dysfunction and regulate mitochondrial fission. However, the roles of PINK1 and Drp1 in hippocampal injury caused by transient global ischemia (TGI) remain unknown. We therefore tested the hypothesis that TGI may induce PINK1 causing downregulation of Drp1 phosphorylation to enhance hippocampal neuronal survival, thus functioning as an endogenous neuroprotective mechanism. We found progressively increased PINK1 expression in the hippocampal CA1 subfield1-48 h following TGI, reaching the maximal level at 4 h. Despite lack of changes in the expression level of total Drp1 and phosphor-Drp1 at Ser637, TGI induced a time-dependent increase of Drp1 phosphorlation at Ser616 that peaked after 24 h. Notably, PINK1-siRNA increased p-Drp1(Ser616) protein level in hippocampal CA1 subfield 24 h after TGI. The PINK1 siRNA also aggravated the TGI-induced oxidative DNA damage with an increased 8-hydroxy-deoxyguanosine (8-OHdG) content in hippocampal CA1 subfield. Furthermore, PINK1 siRNA also augmented TGI-induced apoptosis as evidenced by the increased numbers of TUNEL-positive staining and enhanced DNA fragmentation. These findings indicated that PINK1 is an endogenous protective mediator vital for neuronal survival under ischemic insult through regulating Drp1 phosphorylation at Ser616.
authors: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan. Electronic address: chensd@adm.cgmh.org.tw.
authors: Shang-Der
authors: SD
authors: Chen
authors: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors: Tsu-Kung
authors: TK
authors: Lin
authors: Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors: Ding-I
authors: DI
authors: Yang
authors: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors: Su-Ying
authors: SY
authors: Lee
authors: Department of Psychology, National Cheng Kung University, Tainan, Taiwan.
authors: Fu-Zen
authors: FZ
authors: Shaw
authors: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors: Chia-Wei
authors: CW
authors: Liou
authors: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan. Electronic address: ycchuang@adm.cgmh.org.tw.
authors: Yao-Chung
authors: YC
authors: Chuang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099202:PTEN-Induced Putative Kinase
chemical_list: D034281:Dynamins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C519851:Dnm1l protein, rat
keywords: Drp1; Hippocampus; PINK1; Transient global ischemia