Mitochondria-localized circRNA BRAKE restrains adipogenesis under nutrient overload by disrupting ATP synthase assembly in mice

Abstract Impaired adipogenesis contributes to obesity-associated metabolic disorders, in which mitochondrial dysfunction plays an important role. Emerging evidence suggests that mitochondria-localized circular RNAs (circRNAs) influence mitochondrial function; however, whether they regulate adipogenesis and systemic metabolism is unclear. By profiling circRNAs in mitochondria isolated from the white adipose tissue (WAT) of obese male mice, we observe an upregulation of Birc6 -circRNA Repressing Adipogenesis and Krebs-cycle Energy (BRAKE) in mitochondria. In vivo, adipocyte-specific circRNA BRAKE knockdown in male mice reduces body weight, restricts fat expansion, and improves insulin sensitivity. In vitro studies show that circRNA BRAKE inhibits adipogenesis. Mechanistically, circRNA BRAKE binds ATP5A and disrupts ATP synthase assembly, thereby reducing ATP production and mTORC1 signaling and suppressing adipogenesis. In omental WAT (oWAT) of patients with obesity, mitochondrial circRNA BRAKE levels are elevated and inversely correlated with mitochondrial bioenergetic function. Collectively, our data identify a mitochondria-localized circRNA that regulates energy metabolism and adipogenesis, suggesting that circRNA BRAKE may represent a potential therapeutic target for obesity-related metabolic diseases.