title: Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: the role of inhibition of Drp1 in ischemic brain damage.
abstract: Mitochondria dysfunction is implicated in diverse conditions, including metabolic and neurodegenerative disorders. Mitochondrial dynamics has attracted increasing attention as to its relationship with mitochondria autophagy, also known as mitophagy, which is critical for degradation of dysfunctional mitochondria maintaining mitochondrial homeostasis. Mitochondrial ﬁssion and its role in clearance of injured mitochondria in acute ischemic injury, however, have not been elucidated yet. Here we showed that hypoxic/ischemic conditions led to fragmentation of mitochondria and induction of mitophagy in permanent middle cerebral artery occlusion (pMCAO) rats and oxygen-glucose deprivation (OGD) PC12 cells. Inhibition of Drp1 by pharmacologic inhibitor or siRNA resulted in accumulation of damaged mitochondria mainly through selectively blocking mitophagy without affecting mitochondrial biogenesis and non-selective autophagy. Drp1 inhibitors increased the infarct volume and aggravated the neurological deﬁcits in a rat model of pMCAO. We demonstrated that the devastating role of disturbed mitochondrial fission by inhibiting Drp1 contributed to the damaged mitochondria-mediated injury such as ROS generation, cyt-c release and activation of caspase-3. Taken together, we proved that under hypoxic/ischemic stress a Drp1-dependent mitophagy was triggered which was involved in the removal of damaged mitochondria and cellular survival at the early stage of hypoxic/ischemic injury. Thus, Drp1 related pathway involved in selective removal of dysfunctional mitochondria is proposed as an efficient target for treatment of cerebral ischemia.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, and Neuroscience Center, Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zuo
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, and Neuroscience Center, Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, and Neuroscience Center, Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Cong-Yuan
authors.initials: CY
authors.lastname: Xia
authors.affiliation: Shanxi University of Traditional Chinese Medicine, Taiyuan 030024, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Guo
authors.affiliation: Shanxi University of Traditional Chinese Medicine, Taiyuan 030024, China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: He
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, and Neuroscience Center, Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: chennh@imm.ac.cn.
authors.forename: Nai-Hong
authors.initials: NH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D063306:Mitophagy / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C505410:Casp3 protein, rat; D053148:Caspase 3; C519851:Dnm1l protein, rat; D034281:Dynamins; D005947:Glucose
keywords: Brain ischemia; Damaged mitochondria; Fission; Mitochondrial autophagy