title: PARK2-dependent mitophagy induced by acidic postconditioning protects against focal cerebral ischemia and extends the reperfusion window.
abstract: Prompt reperfusion after cerebral ischemia is critical for neuronal survival. Any strategies that extend the limited reperfusion window will be of great importance. Acidic postconditioning (APC) is a mild acidosis treatment that involves inhaling CO2during reperfusion following ischemia. APC attenuates ischemic brain injury although the underlying mechanisms have not been elucidated. Here we report that APC reinforces ischemia-reperfusion-induced mitophagy in middle cortical artery occlusion (MCAO)-treated mice, and in oxygen-glucose deprivation (OGD)-treated brain slices and neurons. Inhibition of mitophagy compromises neuroprotection conferred by APC. Furthermore, mitophagy and neuroprotection are abolished in Park2 knockout mice, indicating that APC-induced mitophagy is facilitated by the recruitment of PARK2 to mitochondria. Importantly, in MCAO mice, APC treatment extended the effective reperfusion window from 2 to 4 h, and this window was further extended to 6 h by exogenously expressing PARK2. Taken together, we found that PARK2-dependent APC-induced mitophagy renders the brain resistant to ischemic injury. APC treatment could be a favorable strategy to extend the thrombolytic time window for stroke therapy.
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shen
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Wu
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Shousheng
authors.initials: S
authors.lastname: Lu
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: b Department of Pharmacology and Laboratory of Aging and Nervous Diseases , Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, School of Pharmaceutical Science, Soochow University , Suzhou , China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Qin
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Department of Pharmacology , Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University , Hangzhou , China.
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology* / Q000517:prevention & control*; D002245:Carbon Dioxide; D002478:Cells, Cultured; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D057775:Ischemic Postconditioning; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D009474:Neurons / Q000378:metabolism; D000066829:Neuroprotection; D021381:Protein Transport; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology* / Q000517:prevention & control*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D002245:Carbon Dioxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: PARK2; acidic postconditioning; cerebral ischemia; mitophagy; neuroprotection; time window