BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2
BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2
复制标题
BNIP3L/NIX 介导的线粒体自噬可独立于 PARK2 预防缺血性脑损伤
DOI：
10.1080/15548627.2017.1357792
复制
发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Yuan, Yang;Zheng, Yanrong;Chen, Zhong
脑缺血引起大量线粒体损伤。这些受损的线粒体通过线粒体自噬被清除，从而减轻脑损伤。在这里，我们确定了BNIP3L/NIX参与脑缺血再灌注（I-R）诱导的线粒体自噬。Bnip3l基因敲除（Bnip3l−/−）会损害小鼠的线粒体自噬，加重脑I-R损伤，这可以通过Bnip3l过表达来挽救。在I-R后出现线粒体自噬缺陷的park2 - / -小鼠中，BNIP3L过表达可观察到其挽救作用。有趣的是，bnip3l和park2双敲除小鼠在I-R处理下表现出协同的线粒体自噬缺陷，这进一步突出了bnip3l介导的线粒体自噬独立于park2的作用。进一步的实验表明，BNIP3L丝氨酸81的磷酸化对BNIP3L介导的有丝分裂至关重要。在bnip3l−/−小鼠中，非磷酸化突变体BNIP3LS81A无法抵消自噬损伤和神经保护作用。我们的研究结果为缺血性卒中的线粒体质量控制提供了见解，并提出了BNIP3L可能是缺血性卒中的潜在治疗靶点的概念，超出了其在网状细胞成熟中的公认作用。
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.