BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2 |
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Authors: | Yang Yuan Yanrong Zheng Ying Chen Xiaoli Wu Jiaying Wu |
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Institution: | 1. Institute of Pharmacology &2. Toxicology, College of Pharmaceutical Sciences, Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang University, Hangzhou, China |
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Abstract: | Cerebral ischemia induces massive mitochondrial damage. These damaged mitochondria are cleared, thus attenuating brain injury, by mitophagy. Here, we identified the involvement of BNIP3L/NIX in cerebral ischemia-reperfusion (I-R)-induced mitophagy. Bnip3l knockout (bnip3l?/?) impaired mitophagy and aggravated cerebral I-R injury in mice, which can be rescued by BNIP3L overexpression. The rescuing effects of BNIP3L overexpression can be observed in park2?/? mice, which showed mitophagy deficiency after I-R. Interestingly, bnip3l and park2 double-knockout mice showed a synergistic mitophagy deficiency with I-R treatment, which further highlighted the roles of BNIP3L-mediated mitophagy as being independent from PARK2. Further experiments indicated that phosphorylation of BNIP3L serine 81 is critical for BNIP3L-mediated mitophagy. Nonphosphorylatable mutant BNIP3LS81A failed to counteract both mitophagy impairment and neuroprotective effects in bnip3l?/? mice. Our findings offer insights into mitochondrial quality control in ischemic stroke and bring forth the concept that BNIP3L could be a potential therapeutic target for ischemic stroke, beyond its accepted role in reticulocyte maturation. |
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Keywords: | BNIP3L/NIX cerebral ischemia mitophagy PARK2/PARKIN phosphorylation |
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