NDP52 Protects Against Myocardial Infarction-Provoked Cardiac Anomalies Through Promoting Autophagosome-Lysosome Fusion Recruiting TBK1 and RAB7.

Acute myocardial infarction (MI), caused by acute coronary artery obstruction, is a common cardiovascular event leading to mortality. Nuclear dot protein 52 (NDP52) is an essential selective autophagy adaptor, although its function in MI is still obscure. This study was designed to examine the function of NDP52 in MI and the associated mechanisms. Our results revealed that MI challenge overtly impaired myocardial geometry and systolic function, along with cardiomyocyte apoptosis, myocardial interstitial fibrosis, and mitochondrial damage, and NDP52 nullified such devastating responses. Further studies showed that the blockade of mitochondrial clearance is related to MI-induced buildup of damaged mitochondria. Mechanistic approaches depicted that 7-day MI induced abnormal mitophagy flux, resulting in poor lysosomal clearance of injured mitochondria. NDP52 promoted mitophagy flux through the recruitment of Ras-associated protein RAB7 (RAB7) and TANK-binding kinase 1 (TBK1). On protein co-localization, TBK1 phosphorylated RAB7, in line with the finding that chloroquine or a TBK1 inhibitor reversed NDP52-dependent beneficial responses. This study denoted a novel mechanism that NDP52 promotes cardioprotection against ischemic heart diseases through interaction with TBK1 and RAB7, leading to RAB7 phosphorylation, induction of mitophagy to clear ischemia-induced impaired mitochondria, thus preventing cardiomyocyte apoptosis in MI. Our results indicate that NDP52 promotes autophagic flux and clears damaged mitochondria to diminish reactive oxygen species and cell death in a TBK1/RAB7-dependent manner and thus limits MI-induced injury. 36, 1119-1135.