MTX2 facilitates PKM2 tetramerization to promote cardiac glucose metabolism and protects the heart against ischemia/reperfusion injury.

Myocardial ischemia reperfusion (I/R) injury is a major cause of adverse outcomes following revascularization therapy. Although alterations in metabolic activities during reperfusion have been implicated, the molecular mechanisms underlying the pathogenesis of I/R injury remain elusive. Metaxin 2 (MTX2), initially identified as a core component of protein import complexes, has recently been characterized in diverse cellular functions. Nevertheless, its involvement in myocardial I/R injury has yet to be fully elucidated. In this study, we aim to evaluate the role and the underlying mechanism of MTX2 in I/R injury. The myocardial I/R model was established, and the protein levels of MTX2 were determined at different time points following coronary occlusion. Loss-of-function and gain-of-function strategies were applied via genetic ablation or intra-myocardial adenovirus injection to ascertain the role of MTX2 in myocardial I/R injury. RNA sequencing, seahorse metabolic analysis, and mass spectrometry were conducted to uncover the underlying molecular mechanisms. We observed that the expression of MTX2 was significantly decreased in I/R hearts. Tamoxifen-induced cardiomyocyte-specific deletion of led to aggravated myocardial I/R injury, resulting in impaired cardiac oxidative phosphorylation and glycolysis. Mechanistically, dimeric PKM2, a less active pyruvate kinase form compared with tetrameric PKM2, was found to be dramatically accumulated in deficiency mice after myocardial I/R surgery. The TOM37 domain of MTX2 interacted directly with PKM2 to promote PKM2 tetramerization, thereby modulating glucose metabolic flux. Pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, rescued the metabolic and functional outcomes of I/R in deficiency mice. Our results identified, for the first time, a cardioprotective role of MTX2 in modulating cardiac glucose metabolism by facilitating PKM2 tetramerization. Targeting metabolic homeostasis by restoring MTX2 might be a promising therapeutic strategy to mitigate myocardial I/R injury.