Key result
Mitofusin (MFN) inhibitors reduced mitochondrial Ca2+ transfer and myocardial infarct size in mice, even when delayed until reperfusion, whereas MFN activators exacerbated infarct size.
Why the study?
Mitofusin 1 and 2 mediate mitochondrial fusion, and mitofusin 2 also tethers the endoplasmic/sarcoplasmic reticulum to mitochondria, motivating investigation of how peptide-mediated manipulation of mitofusin conformations and inter-organellar interactions regulates myocardial infarct size in mice.
Does pharmacological modulation of mitofusins with cell-permeable peptides reduce myocardial infarct size in mice undergoing reperfused myocardial infarction?
Does pharmacological modulation of mitofusins with cell-permeable peptides reduce myocardial infarct size in mice undergoing reperfused myocardial infarction?
Pharmacological inhibition of mitofusins at reperfusion reduces mitochondrial calcium overload and limits myocardial infarct size in mice, suggesting a potential therapeutic strategy for reperfused myocardial infarction.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for mitofusin-targeted cardioprotection; requires validation in larger models before clinical consideration.
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.
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Axelrod et al. (2026) studied Myocardial infarction in mice. Cell-permeable mitofusin (MFN) modulator peptides (activators and inhibitors) was evaluated on Myocardial infarct size. Mitofusin (MFN) inhibitors reduced mitochondrial Ca2+ transfer and myocardial infarct size in mice, even when delayed until reperfusion, whereas MFN activators exacerbated infarct size.
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