Department of Pharmacology, University of California, San Diego, CA, USA.
Autophagy. 2023 Jun;19(6):1865-1866. doi: 10.1080/15548627.2022.2132707. Epub 2022 Oct 18.
RHOA (ras homolog family member A) is a small G-protein that regulates a range of cellular processes including cell growth and survival. RHOA is a proximal downstream effector of G protein-coupled receptors coupling to GNA12/Gα-GNA13/Gα proteins, and is activated in response to stretch and oxidative stress, functioning as a stress-response molecule. It has been demonstrated that RHOA signaling provides cardioprotection through inhibition of mitochondrial death pathways. Mitochondrial integrity is preserved not only by inhibition of mitochondrial death pathways but also by mitochondrial quality control mechanisms including mitophagy. One of the most well-established mechanisms of mitophagy is the mitochondrial membrane depolarization-dependent PINK1-PRKN/Parkin pathway. However, depolarization of the mitochondrial membrane potential is a late-stage event that occurs just before cell death, and additional intracellular mechanisms that enhance the PINK1-PRKN pathway have not been fully determined. We recently discovered that RHOA activation engages a unique mechanism to regulate PINK1 protein stability without inducing mitochondrial membrane depolarization, leading to increased mitophagy and protection against ischemia in cardiomyocytes. Our results suggest regulation of RHOA signaling as a potential strategy to enhance protective mitophagy against stress without compromising mitochondrial functions.
RHOA（ras 同源家族成员 A）是一种小 G 蛋白，可调节多种细胞过程，包括细胞生长和存活。RHOA 是 G 蛋白偶联受体与 GNA12/Gα-GNA13/Gα 蛋白偶联的近端下游效应物，可被拉伸和氧化应激激活，作为应激反应分子发挥作用。已经证明，RHOA 信号通过抑制线粒体死亡途径提供心脏保护。线粒体完整性不仅通过抑制线粒体死亡途径来维持，还通过包括线粒体自噬在内的线粒体质量控制机制来维持。线粒体自噬最成熟的机制之一是依赖于线粒体膜去极化的 PINK1-PRKN/Parkin 途径。然而，线粒体膜电位去极化是在细胞死亡之前发生的晚期事件，增强 PINK1-PRKN 途径的其他细胞内机制尚未完全确定。我们最近发现，RHOA 激活通过不诱导线粒体膜去极化的独特机制来调节 PINK1 蛋白稳定性，从而导致自噬增加，并在心肌细胞中对抗缺血。我们的研究结果表明，调节 RHOA 信号可能是一种增强应激保护自噬而不损害线粒体功能的潜在策略。
