Mitofusin 1 and mitofusin 2 (MFN1 and MFN2) are best known for mediating mitochondrial fusion through dimerization on adjacent mitochondria. MFN2, but not MFN1, also resides at the endoplasmic reticulum — or sarcoplasmic reticulum in cardiomyocytes — where dimerization of mitofusins on the ER/SR and mitochondrial membranes tethers the two organelles together. These contact sites are the routes through which calcium passes from the ER/SR into mitochondria, a flow carried out by the mitochondrial calcium uniporter, which transports Ca2+ into the mitochondrial matrix.

The researchers found that MFN activators increase ER/SR–mitochondria proximity, promote ER/SR-to-mitochondria calcium transfer and exacerbate infarct size in mice. These effects depended on MFN2 but not MFN1, and on the mitochondrial calcium uniporter, tying the damage directly to enhanced calcium delivery into mitochondria during ischemia-reperfusion injury.

Conversely, MFN inhibitors reduced mitochondrial calcium transfer and infarct size. Notably, although ER/SR–mitochondria proximity was not affected by the inhibitors, their protection persisted even when administration was delayed until the initiation of reperfusion, as shown in the study’s in vivo experiments.

The authors conclude that these findings demonstrate the feasibility of acutely modulating ER/SR–mitochondria interactions and calcium dynamics, and suggest that pharmacological MFN inhibition may provide a new therapeutic strategy to limit cardiac damage during reperfused myocardial infarction. The evidence so far comes from mouse models and cultured cells, including cardiomyocyte-specific Mfn1 and Mfn2 knockout mice and cardiomyocyte-specific Mcu deletion experiments, so translation to human patients remains to be established.

Subject of Research: Pharmacological modulation of mitofusins and ER/SR–mitochondria calcium transfer in mouse myocardial infarction

Article Title: Manipulation of ER–mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice

Article References: Axelrod, J. L., Nichtová, Z., Schneider, T., Lee, J., Pekson, R., Qin, D., Ghazi, M., Kumar, V., Margulets, V., Kirshenbaum, L. A., Santulli, G., Csordás, G., Calvert, J. W., & Kitsis, R. N. (2026). Manipulation of ER–mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice. Nature Cardiovascular Research. https://doi.org/10.1038/s44161-026-00903-6

Image Credits: AI Generated

DOI: 10.1038/s44161-026-00903-6

Keywords: mitofusin, MFN2, mitochondria, endoplasmic reticulum, calcium transfer, myocardial infarction, ischemia-reperfusion, mitochondrial calcium uniporter, cardiomyocytes, infarct size, therapeutic strategy, mice