■外部线粒体RhoGTPase1,MIRO1,介导细胞内的线粒体运动,但对血管平滑肌细胞(VSMC)生理学及其血管内疾病的作用的影响,如血管损伤后的新内膜形成是未知的。
■建立了VSMC中Miro1选择性缺失的体内模型,对动物进行颈动脉结扎。然后通过成像线粒体定位和cr结构并评估对ATP产生的影响,在移植的VSMC中探索与VSMC增殖相关的分子机制。代谢功能和与电子传递链(ETC)组分的相互作用。
■MIRO1在人动脉粥样硬化斑块内的VSMC中强烈表达,并通过在G1/S阻断细胞周期进程促进小鼠的VSMC增殖和新内膜形成,线粒体定位,和PDGF诱导的ATP产生和呼吸;缺乏线粒体活动所需的EF手的MIRO1突变体的过表达并不能完全挽救这些作用。在超微结构层面,Miro1缺失扭曲了线粒体cr,并减少了超复合物的形成和ETC复合物I的活性。
■线粒体运动性对于VSMC增殖至关重要,并且依赖于MIRO1。MIRO1的EF-手调节线粒体的细胞内定位。此外,MIRO1的缺失导致线粒体cr扭曲和ATP生成减少。我们的发现表明运动性与线粒体ATP的产生有关。我们阐明了MIRO1通过调节线粒体影响细胞增殖的两种未知机制:通过Ca2+依赖的EF手管理线粒体放置,第二,通过影响cr结构和ATP合成。
UNASSIGNED: The outer mitochondrial Rho GTPase 1, MIRO1, mediates mitochondrial motility within cells, but implications for vascular smooth muscle cell (VSMC) physiology and its roles invascular diseases, such as neointima formation following vascular injury are widely unknown.
UNASSIGNED: An in vivo model of selective Miro1 deletion in VSMCs was generated, and the animals were subjected to carotid artery ligation. The molecular mechanisms relevant to VSMC proliferation were then explored in explanted VSMCs by imaging mitochondrial positioning and cristae structure and assessing the effects on ATP production, metabolic function and interactions with components of the electron transport chain (ETC).
UNASSIGNED: MIRO1 was robustly expressed in VSMCs within human atherosclerotic plaques and promoted VSMC proliferation and neointima formation in mice by blocking cell-cycle progression at G1/S, mitochondrial positioning, and PDGF-induced ATP production and respiration; overexpression of a MIRO1 mutant lacking the EF hands that are required for mitochondrial mobility did not fully rescue these effects. At the ultrastructural level, Miro1 deletion distorted the mitochondrial cristae and reduced the formation of super complexes and the activity of ETC complex I.
UNASSIGNED: Mitochondrial motility is essential for VSMC proliferation and relies on MIRO1. The EF-hands of MIRO1 regulate the intracellular positioning of mitochondria. Additionally, the absence of MIRO1 leads to distorted mitochondrial cristae and reduced ATP generation. Our findings demonstrate that motility is linked to mitochondrial ATP production. We elucidated two unrecognized mechanisms through which MIRO1 influences cell proliferation by modulating mitochondria: first, by managing mitochondrial placement via Ca2+-dependent EF hands, and second, by affecting cristae structure and ATP synthesis.