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Aberrant expression of mitochondrial proteins impairs cardiac function and causes heart disease. The mechanism of regulation of mitochondria encoded protein expression during cardiac disease, however, remains underexplored. Here, we show that multiple pathogenic cardiac stressors induce the expression of miR‐574 guide and passenger strands (miR‐574‐5p/3p) in both humans and mice. miR‐574 knockout mice exhibit severe cardiac disorder under different pathogenic cardiac stresses while miR‐574‐5p/3p mimics that are delivered systematically using nanoparticles reduce cardiac pathogenesis under disease insults. Transcriptomic analysis of miR‐574‐null hearts uncovers family with sequence similarity 210 member A (FAM210A) as a common target mRNA of miR‐574‐5p and miR‐574‐3p. The interactome capture analysis suggests that FAM210A interacts with mitochondrial translation elongation factor EF‐Tu. Manipulating miR‐574‐5p/3p or FAM210A expression changes the protein expression of mitochondrial‐encoded electron transport chain (ETC) genes but not nuclear‐encoded mitochondrial ETC genes in both human AC16 cardiomyocyte cells and miR‐574‐null murine hearts. Together, we discovered that miR‐574 regulates FAM210A expression and modulates mitochondrial‐encoded protein expression, which may influence cardiac remodeling in heart failure., The findings identify that miR‐574 fine‐tunes FAM210A expression and modulates mitochondrial encoded protein expression, thereby maintaining normal mitochondrial function and protecting the heart from cardiac stress induced pathological remodeling.

Osteoporosis and sarcopenia are common comorbid diseases, yet their shared mechanisms are largely unknown. We found that genetic variation near FAM210A was associated, through large genome-wide association studies, with fracture, bone mineral density (BMD), and appendicular and whole body lean mass, in humans. In mice, Fam210a was expressed in muscle mitochondria and cytoplasm, as well as in heart and brain, but not in bone. Grip strength and limb lean mass were reduced in tamoxifen-inducible Fam210a homozygous global knockout mice (TFam210a−/−), and in tamoxifen-inducible Fam210 skeletal muscle cell-specific knockout mice (TFam210aMus−/−). Decreased BMD, bone biomechanical strength, and bone formation, and elevated osteoclast activity with microarchitectural deterioration of trabecular and cortical bones, were observed in TFam210a−/− mice. BMD of male TFam210aMus−/− mice was also reduced, and osteoclast numbers and surface in TFam210aMus−/− mice increased. Microarray analysis of muscle cells from TFam210aMus−/− mice identified candidate musculoskeletal modulators. FAM210A, a novel gene, therefore has a crucial role in regulating bone structure and function, and may impact osteoporosis through a biological pathway involving muscle as well as through other mechanisms.