Talk abstracts
Talk on Saturday 10:15-10:30am submitted by Jiangbin Wu
MiR-574-FAM210A axis maintains cardiac mitochondrial translational homeostasis
Jiangbin Wu (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY 14586), Kadiam C Venkata Subbaiah (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY 14586), Feng Jiang, (Department of Biochemistry & Biophysics, University of Rochester School of Medicine & Dentistry, Rochester, NY 14586), Omar Hedaya (Department of Biochemistry & Biophysics, University of Rochester School of Medicine & Dentistry, Rochester, NY 14586), Wai Hong Wilson Tang (Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195), Peng Yao (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY 14586)
Abstract:
Prior studies have examined mechanisms that coordinate mRNA transcription of nuclear-encoded mitochondrial genes (NEMGs) and mitochondrial encoded genes (MEGs). However, regulatory mechanisms of MEG mRNA translation and its coupling with NEMG mRNA translation under disease conditions remain underexplored. Here, we have identified a microRNA-574-FAM210A (family with sequence similarity 210 member A) axis that maintains the optimal translation of MEGs and mitochondrial homeostasis in cardiac cells, as a compensatory cardioprotective pathway to prevent heart failure progression. miR-574 knockout mice exhibited an advanced cardiac hypertrophy phenotype associated with increased fibrosis after cardiac stresses. miR-574 produces two functional strands, miR-574-5p and miR-574-3p, which play synergistic cardioprotective role in preventing ventricular pathological remodeling, partially by downregulating a common target mRNA FAM210A. miR-574-5p antagonizes FAM210A expression in cardiac myocytes to prevent excessive MEG expression, enhanced reactive oxygen species production and impaired mitochondrial activity, thereby preventing myocyte hypertrophy. Hypertrophic stress activates exosome-mediated release of miR-574-3p captured by phospho-hnRNP L (heterogeneous nuclear ribonucleoprotein L) and reduces cardiac fibroblast proliferation by targeting FAM210A. Our results also define a critical role of FAM210A in translational control of a specific cohort of cardiac mitochondrial encoded genes. We found that FAM210A, induced in dilated cardiomyopathy and ischemic heart failure patients, is a mitochondrial translational activator within a complex with EF-Tu and ATAD3A to accelerate translation elongation of specific MEGs. Cardiomyocyte-specific knockout of Fam210a in mice leads to mitochondrial dysfunction, myofiber disarray, and spontaneous cardiac hypertrophy. Collectively, we discover a novel miR-574-FAM210A pathway that modulates cardiac mitochondrial translational homeostasis for maintaining cardiac well-being.
Keywords: translational control, miRNA, Fam210a