Mesencephalic Astrocyte‐Derived Neurotrophic Factor Binds BAX to Preserve Mitochondrial Homeostasis and Energy Metabolism for Relieving Myocardial Hypertrophy

Abstract Myocardial hypertrophy (MH) is a heart disease accompanied by mitochondrial energy disorder and oxidative stress for cardiomyocyte apoptosis. Mesencephalic astrocyte‐derived neurotrophic factor (MANF), with anti‐inflammation and cytoprotection, is found to be negatively correlated with atrial apoptosis and fibrillation. Here, the effect and mechanism of MANF on MH are studied. Myocardial cell‐specific MANF knockout (MKO) mice are constructed to establish transverse aortic constriction (TAC) or angiotensin II (Ang II)‐induced MH model. MANF is found to be upregulated by MH and protects cardiomyocytes against TAC or Ang II‐induced MH. Mechanistically, through single‐cell RNA sequencing and metabolomics analysis, MANF in cardiomyocytes is closely involved in glycolysis‐oxidative phosphorylation balance and mitochondrial homeostasis. Furthermore, MANF interacts with pro‐apoptotic BAX to inhibit BAX mitochondrial translocation, subsequently decreasing mitochondrial damage, cytochrome c release, and cardiomyocyte death. These results indicate a promising clinical value of MANF for MH treatment, and also preliminarily define MANF's role in mitochondrial energy production and mitochondria‐associated apoptosis pathway.