Title : Parkin promotes Mic60 ubiquitination to exacerbate myocardial ischemia-reperfusion injury by inducing mitochondrial dysfunction
Abstract:
Reperfusion strategy is the most effective treatment for acute myocardial infarction, but the ischemia-reperfusion injury severely affects clinical benefits of this therapy. Mitochondrial dysfunction is the main cause of cardiomyocyte death due to ischemia-reperfusion, but the molecular mechanism of which remains unknown. We found that the E3 ubiquitin ligase Parkin plays an important role in mitochondrial function. We performed proteome-wide analysis using immunoprecipitation coupled to mass spectrometry, and Mic60 was identified as a novel protein interacting with Parkin. By establishing the hypoxia-reoxygenation injury model in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and the ischemia-reperfusion injury model in cardiac-specific Mic60 knockout mice, we proposed to demonstrate for the first time that mitochondrial inner membrane protein Mic60 is the key substrate for Parkin during myocardial ischemia-reperfusion. The degradation of Mic60 via ubiquitin-proteasome system contributes to the elevation of oxidative stress level, and mediates mitochondrial cristae disorders as well as mitochondrial dysfunction. At the same time, it results in increased level of lipid peroxidation and disturbance in the metabolism of iron ions, leading to ferroptosis in cardiomyocytes, and finally aggravates myocardial ischemia-reperfusion injury. Our project is expected to clarify the molecular mechanism of myocardial ischemia-reperfusion injury, which provids new ideas and strong guarantees for improving the prognosis of patients undergoing reperfusion treatment.
Audience Take Away:
- This project will help to elucidate the molecular regulatory mechanisms of myocardial ischemia-reperfusion injury, discovering novel targets for therapy.And our research is able to provide new ideas to improve the prognosis of patients treated with reperfusion therapy
- Most of the currently reported ubiquitination substrates of Parkin are mitochondrial outer membrane proteins, but our study firstly revealed that Parkin also ubiquitinates the mitochondrial inner membrane protein Mic60. Our discovery expands the possible ubiquitination substrates of Parkin
- Our study contributes to the development of novel targeted drugs for the treatment of myocardial ischemia-reperfusion
