Protective mitochondrial fission induced by stress-responsive protein GJA1-20k.
Protective mitochondrial fission induced by stress-responsive protein GJA1-20k.
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DOI：
10.7554/elife.69207
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发表时间：
2021-10-05
期刊：
影响因子：
7.7
通讯作者：
Shaw RM
中科院分区：
文献类型：
--
作者：
Shimura D;Nuebel E;Baum R;Valdez SE;Xiao S;Warren JS;Palatinus JA;Hong T;Rutter J;Shaw RM
缝隙连接蛋白43间隙连接基因GJA 1具有一个编码外显子，但其mRNA经历内部翻译以产生缝隙连接蛋白43的N-末端截短同种型，其中主要同种型的大小仅为20 kDa（GJA 1 - 20 k）。内源性GJA 1 - 20 k蛋白不是膜结合的，并且已经发现响应于缺血应激而增加，定位于线粒体，并且模拟心脏中的缺血预处理保护。然而，目前尚不清楚GJA 1 - 20 k如何有益于线粒体提供这种保护。在这里，使用人类细胞和小鼠，我们确定GJA 1 - 20 k聚合肌动蛋白周围的线粒体，诱导局灶性收缩部位。线粒体分裂事件发生在GJA 1 - 20 k募集肌动蛋白的约45秒内。有趣的是，GJA 1 - 20 k介导的裂变不依赖于典型的动力蛋白相关蛋白1（DRP 1）。我们发现，GJA 1 - 20 k诱导的较小线粒体减少了活性氧（ROS）的产生，并在心脏中提供了有效的保护，防止缺血再灌注损伤。结果表明，应激响应性内部翻译的GJA 1 - 20 k稳定聚合的肌动蛋白丝以刺激限制缺血-再灌注诱导的心肌梗死的非典型线粒体分裂。
The Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, using human cells and mice, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 s of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin-Related Protein 1 (DRP1). We find that GJA1-20k-induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.