Abstract 18222: FAM210A Regulates Mitochondrial Translation and Maintains Cardiac Mitochondrial Homeostasis

Abstract

Introduction: Mitochondria play a vital role in cellular metabolism and energetics and support cardiac function. FAM210A (family with sequence similarity 210 member A) is a novel hub gene in mouse cardiac remodeling. Human FAM210A mutations are associated with sarcopenia. However, the physiological and molecular function of FAM210A remain elusive in the heart. Hypothesis: We aim to determine the biological and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health. Methods and Results: Tamoxifen-induced conditional knockout of Fam210a in mouse cardiomyocytes (CMs) induced progressive dilated cardiomyopathy and heart failure (HF), ultimately causing mortality. Fam210a deficient CMs exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Moreover, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in CMs at the early stage before contractile dysfunction and HF. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of HF. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced HF. Conclusions: These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal CM contractile function. This study also offers a new therapeutic target for treating ischemic heart disease.