The immunoproteasome subunit β2i ameliorates myocardial ischemia/reperfusion injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.

Mitochondrial dynamics are critical for maintaining mitochondrial morphology and function during cardiac ischemia and reperfusion (I/R). The immunoproteasome complex is an inducible isoform of the proteasome that plays a key role in modulating inflammation and some cardiovascular diseases, but the importance of immunoproteasome catalytic subunit β2i (also known as LMP10 or MECL1) in regulating mitochondrial dynamics and cardiac I/R injury is largely unknown. Here, using β2i-knockout (KO) mice and rAAV9-β2i-injected mice, we discovered that β2i expression and its trypsin-like activity were significantly attenuated in the mouse I/R myocardium and in patients with myocardial infarction (MI). Moreover, β2i-KO mice exhibited greatly enhanced I/R-mediated cardiac dysfunction, infarct size, myocyte apoptosis and oxidative stress accompanied by excessive mitochondrial fission due to Mfn1/2 and Drp1 imbalance. Conversely, cardiac overexpression of β2i in mice injected with recombinant adeno-associated virus 9 (rAAV9)-β2i ameliorated cardiac I/R injury. Mechanistically, I/R injury reduced β2i expression and activity, which increased the expression of the E3 ligase Parkin protein and promoted the degradation of mitofusin 1/2 (Mfn1/2), leading to excessive mitochondrial fission. In conclusion, our data suggest for the first time that β2i exerts a protective role against cardiac I/R injury and that increasing β2i expression may be a new therapeutic option for cardiac ischemic disease in clinical practice. Graphical abstract showing how the immunoproteasome subunit β2i ameliorates myocardial I/R injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.