Mitochon-drial 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, O-linked-N-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.
Bibliographical noteFunding Information:
This work was supported by Brown University Karen T. Romer Undergraduate Teaching and Research Award (to S. M. Adaniya), American Physiological Society (APS) 2017 Shih-Chun Wang Young Investigator Award (to J. O-Uchi), National Heart, Lung, and Blood Institute Grant R01-HL-136757 (to J. O-Uchi), American Heart Association (AHA) Grant 16SDG27260248 (to J. O-Uchi), National Institute of General Medical Sciences Grant U54-GM-115677 (to B. S. Jhun), and AHA Grant 18CDA34110091 (to B. S. Jhun). B. S. Jhun is a recipient of the 2018 New Investigator Award from the APS Cell and Molecular Physiology Section.
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