Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
Nat Rev Cardiol. 2022 Nov;19(11):723-736. doi: 10.1038/s41569-022-00703-y. Epub 2022 May 6.
Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial network is essential for cardiovascular function and adaptation to pathological stressors. Mitochondria undergo fission or fusion in response to various environmental cues, and these dynamic changes are vital for mitochondrial function and health. In particular, mitochondrial fission is closely coordinated with the cell cycle and is linked to changes in mitochondrial respiration and membrane permeability. Another key function of fission is the segregation of damaged mitochondrial components for degradation by mitochondrial autophagy (mitophagy). Mitochondrial fission is induced by the large GTPase dynamin-related protein 1 (DRP1) and is subject to sophisticated regulation. Activation requires various post-translational modifications of DRP1, actin polymerization and the involvement of other organelles such as the endoplasmic reticulum, Golgi apparatus and lysosomes. A decrease in mitochondrial fusion can also shift the balance towards mitochondrial fission. Although mitochondrial fission is necessary for cellular homeostasis, this process is often aberrantly activated in cardiovascular disease. Indeed, strong evidence exists that abnormal mitochondrial fission directly contributes to disease development. In this Review, we compare the physiological and pathophysiological roles of mitochondrial fission and discuss the therapeutic potential of preventing excessive mitochondrial fission in the heart and vasculature.
线粒体是参与调节各种重要细胞过程的细胞器，从 ATP 生成到免疫激活。健康的线粒体网络对于心血管功能和适应病理性应激至关重要。线粒体可以响应各种环境线索发生裂变或融合，这些动态变化对于线粒体功能和健康至关重要。特别是，线粒体裂变与细胞周期密切协调，并与线粒体呼吸和膜通透性的变化相关。裂变的另一个关键功能是将受损的线粒体成分隔离，以便通过线粒体自噬（mitophagy）进行降解。线粒体裂变由大型 GTP 酶 dynamin-related protein 1（DRP1）诱导，并受到复杂的调节。激活需要 DRP1 的各种翻译后修饰、肌动蛋白聚合以及内质网、高尔基体和溶酶体等其他细胞器的参与。线粒体融合的减少也会使平衡向线粒体裂变倾斜。尽管线粒体裂变对于细胞内稳态是必要的，但在心血管疾病中，这一过程经常异常激活。事实上，有强有力的证据表明，异常的线粒体裂变直接导致疾病的发展。在这篇综述中，我们比较了线粒体裂变的生理和病理生理作用，并讨论了预防心脏和血管中过度线粒体裂变的治疗潜力。
