Abstract Body: Background:
Myocardial infarction (MI), a globally lethal condition with limited therapeutic options, causes irreversible cardiomyocyte death despite reperfusion. Mitochondrial bioenergetic and redox homeostasis are critical for cardiomyocyte survival, yet ischemia-induced mitochondrial destabilization drives cardiac deterioration. Emerging evidence implicates m6A epitranscriptomic regulation in mitochondrial dysfunction, highlighting its potential as a therapeutic target.
Aims：
This study aims to elucidate the cardioprotective role of N6-methyladenosine（m6A） demethylase fat mass and obesity-associated protein （FTO） in myocardial injury repair post-MI through in vivo and in vitro models, specifically exploring its regulation of mitochondrial calcium uniporter (MCU) and associated mitochondrial dysfunction mechanisms.
Methods：
Clinical human specimens, murine MI models, and primary cardiomyocytes were analyzed. FTO expression was modulated via AAV9 (in vivo) and adenovirus/siRNAs (in vitro). Multi-omics profiling (m6A-seq and MeRIP-qPCR) identified FTO-m6A targets.
Results：
Compared with normal myocardium, infarcted myocardium exhibited decreased FTO expression and elevated m6A methylation levels. FTO knockdown exacerbated mitochondrial dysfunction and cardiomyocyte apoptosis, whereas FTO overexpression rescued oxygen-glucose deprivation (OGD)-induced mitochondrial defects and apoptosis. Integrated m6A-seq and MeRIP-qPCR analyses revealed elevated m6A deposition and expression of mitochondrial calcium uniporter (MCU) mRNA post-MI. MCU silencing ameliorated OGD-induced mitochondrial injury and apoptosis. Mechanistically, FTO deficiency increased m6A modification on MCU mRNA to enhance its stability, while FTO overexpression promoted MCU mRNA decay via m6A demethylation, thereby attenuating mitochondrial dysfunction. Notably, MCU overexpression abolished the cardioprotective effects of FTO.
Conclusion：
FTO mediates cardiac repair following myocardial infarction through m6A demethylation of MCU mRNA，which suppresses pathological calcium overload by enhancing transcript decay. This FTO-m6A-MCU regulatory axis constitutes a mechanistically defined therapeutic target for mitigating ischemic cardiomyocyte injury.