Department of Basic Sciences, Lawrence D. Longo, MD Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California, United States.
Am J Physiol Cell Physiol. 2024 Feb 1;326(2):C442-C448. doi: 10.1152/ajpcell.00354.2023. Epub 2023 Nov 27.
Smooth muscle cells transition reversibly between contractile and noncontractile phenotypes in response to diverse influences, including many from mitochondria. Numerous molecules including myocardin, procontractile miRNAs, and the mitochondrial protein prohibitin-2 promote contractile differentiation; this is opposed by mitochondrial reactive oxygen species (mtROS), high lactate concentrations, and metabolic reprogramming induced by mitophagy and/or mitochondrial fission. A major pathway through which vascular pathologies such as oncogenic transformation, pulmonary hypertension, and atherosclerosis cause loss of vascular contractility is by enhancing mitophagy and mitochondrial fission with secondary effects on smooth muscle phenotype. Proproliferative miRNAs and the mitochondrial translocase TOMM40 also attenuate contractile differentiation. Hypoxia can initiate loss of contractility by enhancing mtROS and lactate production while simultaneously depressing mitochondrial respiration. Mitochondria can reduce cytosolic calcium by moving it across the inner mitochondrial membrane via the mitochondrial calcium uniporter, and then through mitochondria-associated membranes to and from calcium stores in the sarcoplasmic/endoplasmic reticulum. Through these effects on calcium, mitochondria can influence multiple calcium-sensitive nuclear transcription factors and genes, some of which govern smooth muscle phenotype, and possibly also the production of genomically encoded mitochondrial proteins and miRNAs (mitoMirs) that target the mitochondria. In turn, mitochondria also can influence nuclear transcription and mRNA processing through mitochondrial retrograde signaling, which is currently a topic of intensive investigation. Mitochondria also can signal to adjacent cells by contributing to the content of exosomes. Considering these and other mechanisms, it is becoming increasingly clear that mitochondria contribute significantly to the regulation of smooth muscle phenotype and differentiation.
平滑肌细胞在多种因素的影响下可发生可逆的收缩型和非收缩型表型转变，其中包括许多来自线粒体的因素。许多分子，包括肌球蛋白、促收缩的 microRNA 和线粒体蛋白 prohibitin-2，促进收缩型分化；而线粒体活性氧（mtROS）、高浓度的乳酸、自噬和/或线粒体分裂诱导的代谢重编程则会抑制收缩型分化。血管病变（如致癌转化、肺动脉高压和动脉粥样硬化）导致血管收缩性丧失的一个主要途径是通过增强自噬和线粒体分裂，从而对平滑肌表型产生次级影响。促增殖的 microRNA 和线粒体转位酶 TOMM40 也会减弱收缩型分化。缺氧可通过增强 mtROS 和乳酸的产生来启动收缩性丧失，同时抑制线粒体呼吸。线粒体可以通过线粒体钙单向转运体将钙离子从细胞质转移到线粒体内膜，然后通过线粒体相关膜在线粒体钙库和肌浆/内质网钙库之间穿梭，从而降低细胞质中的钙离子。通过这些对钙离子的影响，线粒体可以影响多种钙离子敏感的核转录因子和基因，其中一些基因调控平滑肌表型，并且可能还调控基因组编码的线粒体蛋白和 microRNA（mitoMirs），这些蛋白和 microRNA 靶向线粒体。反过来，线粒体也可以通过线粒体逆行信号转导影响核转录和 mRNA 加工，这是目前研究的热点。线粒体还可以通过贡献外泌体的内容来向相邻细胞发出信号。考虑到这些和其他机制，越来越明显的是，线粒体对平滑肌表型和分化的调节有重要贡献。
