Integrative spatiotemporal analysis uncovers an Fto-mediated epigenetic-metabolic axis governing myocardial ischemic injury.
Source: PubMed, NCBI / U.S. National Library of Medicine
Fat mass and obesity-associated protein (Fto), a pivotal RNA N-methyladenosine (mA) demethylase, is critically involved in the progression of myocardial infarction (MI). However, the role of Fto in MI remains controversial; divergent observation timeframes and unclarified cell-type specificity hinder consensus on its post-MI expression profile and biological functions. In this study, by integrating transcriptomic and single-nucleus sequencing data, we revealed that post-MI Fto downregulation predominantly targets cardiomyocytes and facilitates their apoptosis in an mA-dependent manner. In vitro, Fto knockdown promoted mA levels, impaired mitochondrial ATP synthesis, and drove oxidative stress and apoptosis. Overexpression of Fto rescued OGD-induced mitochondrial dysfunction and apoptosis. Interestingly, the mA inhibitor cycloleucine reversed Fto deficiency-induced mitochondrial dysfunction, confirming that Fto regulates cardiac metabolism and apoptosis in an mA-dependent manner. In vivo, AAV9-mediated cardiac-specific overexpression of Fto protected against MI injury by improving cardiac function and attenuating fibrosis and apoptosis. In conclusion, this study constructed the first single-cell spatiotemporal expression map of Fto after myocardial infarction, resolving previous contradictory findings regarding Fto's biological function. We demonstrated that Fto deficiency aggravates ischemic injury via mA-mediated mitochondrial dysfunction and apoptosis, identifying Fto as a
Abstract
Fat mass and obesity-associated protein (Fto), a pivotal RNA N-methyladenosine (mA) demethylase, is critically involved in the progression of myocardial infarction (MI). However, the role of Fto in MI remains controversial; divergent observation timeframes and unclarified cell-type specificity hinder consensus on its post-MI expression profile and biological functions. In this study, by integrating transcriptomic and single-nucleus sequencing data, we revealed that post-MI Fto downregulation predominantly targets cardiomyocytes and facilitates their apoptosis in an mA-dependent manner. In vitro, Fto knockdown promoted mA levels, impaired mitochondrial ATP synthesis, and drove oxidative stress and apoptosis. Overexpression of Fto rescued OGD-induced mitochondrial dysfunction and apoptosis. Interestingly, the mA inhibitor cycloleucine reversed Fto deficiency-induced mitochondrial dysfunction, confirming that Fto regulates cardiac metabolism and apoptosis in an mA-dependent manner. In vivo, AAV9-mediated cardiac-specific overexpression of Fto protected against MI injury by improving cardiac function and attenuating fibrosis and apoptosis. In conclusion, this study constructed the first single-cell spatiotemporal expression map of Fto after myocardial infarction, resolving previous contradictory findings regarding Fto's biological function. We demonstrated that Fto deficiency aggravates ischemic injury via mA-mediated mitochondrial dysfunction and apoptosis, identifying Fto as a viable clinical target for MI.