Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota , Minneapolis, Minnesota.
Cardiovascular Research Center, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University , Providence, Rhode Island.
Am J Physiol Cell Physiol. 2019 May 1;316(5):C583-C604. doi: 10.1152/ajpcell.00523.2018. Epub 2019 Feb 13.
Mitochondrial fragmentation frequently occurs in chronic pathological conditions as seen in various human diseases. In fact, abnormal mitochondrial morphology and mitochondrial dysfunction are hallmarks of heart failure (HF) in both human patients and HF animal models. A link between mitochondrial fragmentation and cardiac pathologies has been widely proposed, but the physiological relevance of mitochondrial fission and fusion in the heart is still unclear. Recent studies have increasingly shown that posttranslational modifications (PTMs) of fission and fusion proteins are capable of directly modulating the stability, localization, and/or activity of these proteins. These PTMs include phosphorylation, acetylation, ubiquitination, conjugation of small ubiquitin-like modifier proteins, -linked--acetyl-glucosamine glycosylation, and proteolysis. Thus, understanding the PTMs of fission and fusion proteins may allow us to understand the complexities that determine the balance of mitochondrial fission and fusion as well as mitochondrial function in various cell types and organs including cardiomyocytes and the heart. In this review, we summarize present knowledge regarding the function and regulation of mitochondrial fission and fusion in cardiomyocytes, specifically focusing on the PTMs of each mitochondrial fission/fusion protein. We also discuss the molecular mechanisms underlying abnormal mitochondrial morphology in HF and their contributions to the development of cardiac diseases, highlighting the crucial roles of PTMs of mitochondrial fission and fusion proteins. Finally, we discuss the future potential of manipulating PTMs of fission and fusion proteins as a therapeutic strategy for preventing and/or treating HF.
线粒体碎片化在各种人类疾病中慢性病理条件下经常发生。事实上，异常的线粒体形态和线粒体功能障碍是心力衰竭（HF）患者和 HF 动物模型的标志。线粒体碎片化和心脏病变之间的联系已被广泛提出，但线粒体分裂和融合在心脏中的生理相关性仍不清楚。最近的研究越来越表明，分裂和融合蛋白的翻译后修饰（PTMs）能够直接调节这些蛋白的稳定性、定位和/或活性。这些 PTMs 包括磷酸化、乙酰化、泛素化、小泛素样修饰蛋白的缀合、-连接的--乙酰葡萄糖胺糖基化和蛋白水解。因此，了解分裂和融合蛋白的 PTMs 可以帮助我们理解决定线粒体分裂和融合以及包括心肌细胞和心脏在内的各种细胞类型和器官中线粒体功能平衡的复杂性。在这篇综述中，我们总结了目前关于心肌细胞中线粒体分裂和融合的功能和调节的知识，特别关注每个线粒体分裂/融合蛋白的 PTMs。我们还讨论了 HF 中线粒体形态异常的分子机制及其对心脏疾病发展的贡献，强调了线粒体分裂和融合蛋白的 PTMs 的关键作用。最后，我们讨论了操纵 PTMs 的未来潜力作为预防和/或治疗 HF 的治疗策略。
