Psmb8 inhibits mitochondrial fission and alleviates myocardial ischaemia/reperfusion injury by targeting Drp1 degradation

The mitochondrial dynamic imbalance is an important cause of myocardial ischaemia/reperfusion (I/R) injury and dysfunction. Psmb8, as one of the immunoproteasome catalytic subunits, is a key regulator of protein homeostasis, inflammation and some cardiac diseases. Here, we found that the expression level and activity of Psmb8 were significantly reduced in I/R mice and in subjects with myocardial infarction. Cardiomyocyte-specific Psmb8 overexpression in mice markedly ameliorated I/R-mediated cardiac injury and dysfunction, which was accompanied by reduced mitochondrial division via the downregulation of dynamin-related protein-1 (Drp1). However, Psmb8 knockout (KO) mice exhibited the opposite changes. The effects of Psmb8 on mitochondrial fission and apoptosis was confirmed in primary cardiomyocytes with overexpression or knockdown of Psmb8 in vitro. Mechanistically, Psmb8 was directly associated with Drp1 and enhanced its degradation, which subsequently suppressed I/R-mediated mitochondrial fission and cardiac injury. Conversely, knockdown of Drp1 in Psmb8-KO mice restored I/R-induced cardiac dysfunction and mitochondrial dynamic imbalance. Our study identified a new cardioprotective role of Psmb8 in cardiac I/R damage through targeting Drp1, and highlight that increasing Psmb8 activity may constitute a promising therapy for ischaemic heart disease.