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

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.