Mitofusin2 ameliorates ischemia-induced injury and serves as a biomarker for a diagnostic nomogram in ischemic cardiomyopathy

To integrate clinical findings with mechanistic exploration to elucidate the role, potential mechanisms, and clinical translational value of Mitofusin2 (Mfn2) in ischemic cardiomyopathy (ICM). A case–control study was conducted involving 1092 patients with ICM and 960 healthy controls to investigate the association between plasma levels of Mfn2, genetic polymorphisms, and ICM. A nomogram was constructed and its performance was evaluated. Subsequently, an ICM rat model was established by ligating the left anterior descending artery and inducing overexpression of Mfn2 via direct intramyocardial injection of adeno-associated virus serotype 9 (AAV-9). An ischemia-hypoxia-induced model cardiomyocyte injury in H9c2 cells was established using conditioned medium in a tri-gas incubator, and Mfn2 overexpression was achieved via Mfn2 viral transfection. Cardiac function, pathological changes, apoptosis, mitochondrial-associated endoplasmic reticulum membrane (MAMs) integrity, endoplasmic reticulum stress (ERS), and mitochondrial reactive oxygen species (mitoROS) were assessed. Lower plasma Mfn2 levels and mutations in rs1042842 (from AA to AG + GG) and rs2295281 (from CC to CT + TT) were independent predictors of ICM. The developed integrative nomogram demonstrated good discrimination, calibration, and favorable net clinical benefit. In the ICM rat model and ischemia-hypoxia-induced H9c2 cells, Mfn2 expression was significantly downregulated under ICM conditions. Overexpression of Mfn2 was associated with attenuation of cardiac dysfunction, preserved MAMs integrity, and reduced levels of mitoROS, ERS, and apoptosis. Circulating Mfn2 acts as an independent protective biomarker, whereas rs1042842 and rs2295281 polymorphisms are associated with increased susceptibility to ICM. Mfn2 overexpression in cardiac tissues exerts a cardioprotective effect on ICM, and was associated with reduced apoptosis and mitoROS, alleviated ERS, and restored MAMs integrity. This study clarifies the cardioprotective role of Mfn2 and provides a potential integrated tool for ICM diagnosis.