Mitochondria-associated endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) membranes (MAMs) facilitate exchange between these organelles and have been implicated in ATP availability and calcium handling. Previously, we have shown that ischemic/hypoxic injury reduces the distance between the ER/SR and mitochondria, contributing to arrhythmic risk after myocardial infarction (MI). In this study, we explored the mechanism whereby these two membranes are approximated after MI. MI was induced in wild-type C57BL/6J mice by ligation of the left anterior descending coronary artery. Mice were studied at three weeks after MI. Proximity ligation assay (PLA) and electron microscopy (EM) were employed to determine membrane approximation. Among GRP75, MFN2, PTPIP51/VAPB, FIS1/BAP31, and FUNDC1 protein complexes known to mediate MAM approximation, only PTPIP51 protein expression significantly increased by 23% in the MI mice border zone (BZ) and by 141% in human heart tissue from ischemic cardiomyopathic patients. PTPIP51 shRNA delivered by AAV9 was used to downregulate PTPIP51 protein in mouse MI hearts. After PTPIP51 reduction, MI failed to reduce the closest distance between the junctional SR and mitochondria. c-Src and its active form (phosphorylated Src, p-Src) are upstream of PTPIP51 activation and were increased in ischemic cardiomyopathic tissue from mice of humans. The Src inhibitor, PP1, could down-regulated PTPIP51 and also prevented the approximation of junctional SR and mitochondria after MI. In a heterologous expression system (HEK293T Cells), activation of c-Src by CSK inhibition could upregulate PTPIP51, which tightened mitochondrial-SR contact. c-Src mediated upregulation of PTPIP51 after MI caused mitochondrial/SR approximation. Since this approximation contributes to arrhythmic risk after MI, reducing c-Src or PTPIP51 after MI may be novel antiarrhythmic strategies.
Xie et al. (Sun,) studied this question.