We found that hearts deficient in both Mfn1 and Mfn2 were resistant to acute myocardial infarction, and that this cardioprotective phenotype was due to beneficial effects on mitochondrial Ca2+ levels, oxidative stress, and MPTP opening – key mediators of cardiomyocyte death in the setting of acute I/R injury. Here, MFN2 is linked to myocardial infarction.