Abstract 12253: Fam210a Maintains Cardiac Mitochondrial Homeostasis by Promoting Ca 2+ Efflux

Abstract

Mitochondria play fundamental roles in maintaining cellular metabolism and energetics and supporting normal myocardial function. Disturbed cardiac mitochondrial homeostasis causes m itochondrial dysfunction associated with c ardiomyopathy (MC) in humans and mice. Recent genome-wide association studies discovered that the mutations of FAM210A (family with sequence similarity 210 member A) are associated with sarcopenia. Intriguingly, FAM210A is most highly expressed in the heart, and multi-omics analyses in mouse hearts reveal Fam210a as a hub gene in cardiac hypertrophy and remodeling. However, the physiological and molecular functions of FAM210A in the heart remain elusive. Here, we discover that cardiomyocyte (CM) specific knockout (KO) of Fam210a in adult mice leads to progressive dilated cardiomyopathy and heart failure, ultimately causing mortality at ~10 weeks after Fam210a KO. The Fam210a deficient CMs exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of MC. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in CMs at the early stage prior to contractile dysfunction and heart failure. Transcriptomic, proteomic and metabolomic analyses from Fam210a KO hearts indicate that FAM210A deficiency activates chronic integrated stress response (ISR), resulting in metabolic and translational reprogramming in the heart. Therefore, persistent ISR activation contributes to the pathogenesis in MC and progression of heart failure. Mechanistically, interactome and biochemical analyses show that FAM210A binds to mitochondrial Ca 2+ /H + exchanger LETM1 (leucine zipper and EF-hand containing transmembrane protein 1) and promotes LETM1-mediated mitochondrial Ca 2+ efflux. Our evidence suggests that FAM210A is a novel mitochondrial Ca 2+ efflux regulator required for maintaining cardiac mitochondrial homeostasis and offers new targets for treating mitochondrial disease. This work uncovers important interplay among mitochondrial Ca 2+ signaling, metabolic reprogramming, and translational control in cardiac health and disease.