Manipulation of ER-mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial...

Mitofusin (MFN) 1 and MFN2 are large outer mitochondrial membrane GTPases. Dimerization of MFNs on adjacent mitochondria mediates mitochondrial fusion. MFN2, but not MFN1, also resides at the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) membrane, and dimerization of MFNs on ER/SR and mitochondria tethers the two organelles. Here we report that cell-permeable peptides that perturb MFN conformations regulate myocardial infarct size by impacting ER/SR-mitochondria interactions and Ca²⁺ transfer independently of changes in mitochondrial fusion. MFN activators increase ER/SR-mitochondria proximity, promote ER/SR to mitochondria Ca²⁺ transfer and exacerbate infarct size in mice, with effects dependent on MFN2, but not MFN1, and on mitochondrial calcium uniporter, which transports Ca²⁺ into the mitochondrial matrix. Conversely, although ER/SR-mitochondria proximity is not affected, MFN inhibitors reduce mitochondrial Ca²⁺ transfer and infarct size, even when their administration is delayed until reperfusion. These findings demonstrate the feasibility of acutely modulating ER/SR-mitochondria interactions and Ca²⁺ dynamics and suggest that pharmacological MFN inhibition may provide a new therapeutic strategy to limit cardiac damage during reperfused myocardial infarction.