Mitochondrial Fission Regulator 1-Like Protein Protects the Heart from Ischemia/Reperfusion Injury via Dual...

Mitochondrial dysfunction is pivotal in the pathogenesis of cardiac ischemia/reperfusion (I/R) injury. Restoring mitochondrial function represents a promising strategy for mitigating I/R-induced cardiac injury. Mitochondrial fission regulator 1-like protein (MTFR1L), a recently identified mitochondrial dynamics protein, is abundantly expressed in the cardiac tissues. However, its functional role in I/R injury remains undefined. Here, Mtfr1l-knockout mice and human embryonic-stem-cell-derived cardiomyocytes are utilized to investigate the role of MTFR1L in myocardial I/R injury and elucidate its contribution to mitochondrial integrity and function. MTFR1L deficiency markedly worsened I/R-induced cardiac injury and mitochondrial dysfunction. These phenotypes were partially reversed by mitochondria-anchored apoptosis-inducing factor (AIF) overexpression. Mechanistically, MTFR1L protects the heart via 2 interconnected pathways. First, MTFR1L sustains AIF dimerization and stabilizes the AIF-CHCHD4 (coiled-coil-helix-coiled-coil-helix domain containing 4) complex, thereby preserving mitochondrial contact site and cristae organizing system integrity and cristae architecture to facilitate electron transport chain supercomplex assembly, sustain mitochondrial respiration, and limit reactive oxygen species production. Second, by physically interacting with AIF, MTFR1L prevents its mitochondrial release and nuclear translocation, thereby suppressing intrinsic apoptosis. Overall, these findings identify MTFR1L as a cardioprotective protein against myocardial I/R injury through a dual mechanism, providing new insights into the functional repertoire of MTFR1L beyond its previously recognized role in mitochondrial dynamics. Targeting MTFR1L or its interactors may offer novel therapeutic strategies for alleviating mitochondrial dysfunction and myocardial injury.