Ischemia/reperfusion-induced MiD51 upregulation recruits Drp1 to mitochondria and contributes to myocardial injury.

The translocation of Drp1 from the cytosol to mitochondria leads to Drp1 activation and mitochondrial fission in myocardial ischemia/reperfusion (MI/R). However, the molecular mechanism underlying mitochondrial Drp1 translocation remains poorly understood. Mitochondrial Drp1 recruitment relies on 4 binding partners including MiD49, MiD51, Mff and Fis1. This study was to elucidate which one facilitate mitochondrial Drp1 translocation and its role in MI/R injury. MI/R was induced by ligating the left anterior descending coronary artery for 30 min and subsequent reperfusion for 3 h. Primary neonatal cardiomyocytes were subjected to hypoxia for 2 h and reoxygenation for 4 h. SiRNA or Adeno-associated virus (AAV) expressing shRNA was used to knock down the key binding partner in vitro or in vivo respectively. The expression of MiD51 rather than other binding partners (MiD49, Mff or Fis1) was increased after MI/R. MiD51 knockdown inhibited hypoxia/reoxygenation (H/R) or ischemia/reperfusion (I/R)-induced mitochondrial Drp1 translocation. SiRNA-induced knockdown of MiD51 suppressed mitochondrial oxidative stress, improved mitochondrial function and alleviate cellular injury in H/R cardiomyocytes. AAV-mediated knockdown of MiD51 reduced myocardial injury and improved cardiac function in the I/R hearts, while mitochondrial Drp1 translocation and cardiac function were not affected by MiD51 knockdown in the hearts without I/R. MiD51 is identified as the binding partner that promotes mitochondrial Drp1 translocation and contributes to MI/R injury. Inhibition of MiD51 may be a potential therapeutic target to alleviate MI/R injury.