Abstract 327: MicroRNA-574-FAM210A Axis Maintains Mitochondrial Translational Homeostasis and Influences Pathological Cardiac Remodeling

Abstract

Rationale: Translational control is a critical regulatory step in altering protein synthesis under disease conditions. Aberrant synthesis of mitochondrial proteins impairs cardiac function and causes heart disease. However, the mechanism of translational control in mitochondria and during cardiac disease remains underexplored. Objective: We have found that multiple pathogenic cardiac stressors induce the expression of miR-574 guide and passenger strands (miR-574-5p/3p) in humans and mice. Here, we aim to define a new miR-574-FAM210A axis that regulates cardiac mitochondrial translational homeostasis and prevents adverse cardiac remodeling. Methods and Results: Echocardiography, histology and biochemical analyses were used to evaluate the cardiac function of miR-574 knockout mice, which exhibit severe cardiac hypertrophy, fibrosis, and cardiac dysfunction under heart failure-triggering stresses. miR-574-5p/3p mimics that were delivered systematically using nanoparticles reduced cardiac pathogenesis with disease insults. Transcriptome analysis of miR-574-null hearts has uncovered FAM210A as a common target mRNA for miR-574-5p/3p. Interactome and translational state analyses identify a FAM210A-bearing trimeric complex that promotes the translation of mitochondrial encoded electron transport chain genes and modulates mitochondrial activities. Moreover, the phenotypic characterization of tamoxifen-inducible CM-specific Fam210a knockout mice suggests that FAM210A plays a critical role in maintaining normal cardiac mitochondrial morphology and function as well as cardiac health and organismal viability. Conclusions: miR-574-5p and miR-574-3p protect against pathological cardiac remodeling through regulation of FAM210A, a key translational control factor of mitochondrial encoded genes. Thus, we discovered a novel miR-574-FAM210A pathway that modulates cardiac mitochondrial translational homeostasis and influences cardiac remodeling in heart failure.