Parkin Protects against Oxygen-Glucose Deprivation/Reperfusion Insult by Promoting Drp1 Degradation.
Ischemic stroke results in severe brain damage and remains one of the leading causes of death and disability worldwide. Effective neuroprotective therapies are needed to reduce brain damage resulting from ischemic stroke. Mitochondria are crucial for cellular energy production and homeostasis. Modulation of mitochondrial function mediates neuroprotection against ischemic brain damage. Dynamin-related protein 1 (Drp1) and parkin play a key role in regulating mitochondrial dynamics. They are potential therapeutic targets for neuroprotection in ischemic stroke. Protective effects of parkin-Drp1 pathway on mitochondria were assessed in a cellular ischemia-reperfusion injury model. Mouse neuroblastoma Neuro2a (N2a) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. OGDR induces mitochondrial fragmentation. The expression of Drp1 protein is increased after OGDR insult, while the parkin protein level is decreased. The altered protein level of Drp1 after OGDR injury is mediated by parkin through ubiquitin proteasome system (UPS). Drp1 depletion protects against OGDR induced mitochondrial damage and apoptosis. Meanwhile, parkin overexpression protects against OGDR induced apoptosis and mitochondrial dysfunction, which is attenuated by increased expression of Drp1. Our data demonstrate that parkin protects against OGDR insult through promoting degradation of Drp1. This neuroprotective potential of parkin-Drp1 pathway against OGDR insult will pave the way for developing novel neuroprotective agents for cerebral ischemia-reperfusion related disorders.
Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Department of Neurology, The Second People's Hospital of Hunan Province, Changsha, Hunan 410007, China.
Jiayu
J
Tang
Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Zhiping
Z
Hu
National Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
Jieqiong
J
Tan
Department of Neurology, The Second People's Hospital of Hunan Province, Changsha, Hunan 410007, China.
Sonlin
S
Yang
Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Liuwang
0000-0002-8276-6194
L
Zeng
D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; C486391:Dnm1l protein, mouse; D034281:Dynamins; D005947:Glucose; D010100:Oxygen