RhoA signaling increases mitophagy and protects cardiomyocytes against ischemia by stabilizing PINK1 protein and recruiting Parkin to mitochondria.
RhoA signaling increases mitophagy and protects cardiomyocytes against ischemia by stabilizing PINK1 protein and recruiting Parkin to mitochondria.
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RhoA信号通过稳定PINK1蛋白和招募Parkin到线粒体，增加有丝分裂，保护心肌细胞免受缺血。
DOI：
10.1038/s41418-022-01032-w
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发表时间：
2022-12
影响因子：
12.4
通讯作者：
Miyamoto, Shigeki
中科院分区：
文献类型：
--
作者：
Tu, MichelleZ;Tan, Valerie P.;Yu, Justin D.;Tripathi, Raghav;Bigham, Zahna;Barlow, Melissa;Smith, Jeffrey M.;Brown, Joan Heller;Miyamoto, Shigeki
线粒体自噬是线粒体特异性自噬的一种形式，它可以去除功能失调的线粒体，因此是线粒体质量控制的重要过程。pten诱导的激酶1 （PINK1）和E3泛素连接酶Parkin是参与应激诱导的有丝分裂的关键分子，但调控这一途径的细胞内信号传导机制尚不清楚。我们验证了RhoA（一种小GTPase）的信号传导通过调节PINK1/Parkin通路诱导有丝分裂作为抗缺血应激的保护机制的假设。我们证明了组成活性RhoA的表达以及鞘氨醇-1-磷酸诱导的内源性RhoA在心肌细胞中的激活导致线粒体PINK1的积累。这伴随着Parkin易位到线粒体和线粒体蛋白泛素化，导致自噬体及其溶酶体降解对线粒体的识别。心肌细胞中RhoA的表达对缺血具有保护作用，而sirna介导的PINK1敲低会减弱这种心脏保护作用。体内心肌梗死引起线粒体PINK1、Parkin和泛素化线粒体蛋白的增加。aav9介导的RhoA表达增强了这些反应，并观察到梗死面积同时减小。有趣的是，响应RhoA信号诱导线粒体PINK1积累既不通过其转录上调介导，也不依赖于线粒体膜的去极化，而去极化是PINK1积累的典型机制。相反，我们的研究结果表明RhoA信号抑制PINK1切割，从而稳定线粒体中的PINK1蛋白。我们进一步发现，活跃的RhoA定位于线粒体，并与PINK1相互作用，RhoA的线粒体定位受其下游效应蛋白激酶d的调节。这些发现表明，RhoA的激活参与了一种独特的机制，可以调节PINK1的积累，诱导线粒体自噬，防止缺血应激，并暗示RhoA信号的调节是一种潜在的策略，可以增强线粒体自噬，并在应激条件下提供保护。
Mitophagy, a mitochondria-specific form of autophagy, removes dysfunctional mitochondria and is hence an essential process contributing to mitochondrial quality control. PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin are critical molecules involved in stress-induced mitophagy, but the intracellular signaling mechanisms by which this pathway is regulated are unclear. We tested the hypothesis that signaling through RhoA, a small GTPase, induces mitophagy via modulation of the PINK1/Parkin pathway as a protective mechanism against ischemic stress. We demonstrate that expression of constitutively active RhoA as well as sphingosine-1-phosphate induced activation of endogenous RhoA in cardiomyocytes result in an accumulation of PINK1 at mitochondria. This is accompanied by translocation of Parkin to mitochondria and ubiquitination of mitochondrial proteins leading to recognition of mitochondria by autophagosomes and their lysosomal degradation. Expression of RhoA in cardiomyocytes confers protection against ischemia, and this cardioprotection is attenuated by siRNA-mediated PINK1 knockdown. In vivo myocardial infarction elicits increases in mitochondrial PINK1, Parkin, and ubiquitinated mitochondrial proteins. AAV9-mediated RhoA expression potentiates these responses and a concurrent decrease in infarct size is observed. Interestingly, induction of mitochondrial PINK1 accumulation in response to RhoA signaling is neither mediated through its transcriptional upregulation nor dependent on depolarization of the mitochondrial membrane, the canonical mechanism for PINK1 accumulation. Instead, our results reveal that RhoA signaling inhibits PINK1 cleavage, thereby stabilizing PINK1 protein at mitochondria. We further show that active RhoA localizes at mitochondria and interacts with PINK1, and that the mitochondrial localization of RhoA is regulated by its downstream effector protein kinase D. These findings demonstrate that RhoA activation engages a unique mechanism to regulate PINK1 accumulation, induce mitophagy and protect against ischemic stress, and implicates regulation of RhoA signaling as a potential strategy to enhance mitophagy and confer protection under stress conditions.
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影响因子：
3.4
作者：
Miyamoto, Shigeki;Del Re, Dominic P.;Xiang, Sunny Y.;Zhao, Xia;Florholmen, Geir;Brown, Joan Heller
通讯作者：
Brown, Joan Heller
DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin SM;Lazarou M;Wang C;Kane LA;Narendra DP;Youle RJ
通讯作者：
Youle RJ
DOI：
10.1073/pnas.1113248109
发表时间：
2012-04-17
影响因子：
11.1
作者：
Johnson, Bethann N.;Berger, Alison K.;LaVoie, Matthew J.
通讯作者：
LaVoie, Matthew J.
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
4.8
作者：
Hanna, Rita A.;Quinsay, Melissa N.;Gustafsson, Asa B.
通讯作者：
Gustafsson, Asa B.