DAMAGES TO THE ENDOPLASMIC RETICULUM-MITOCHONDRIA INTERACTION IN A TYPE-2 MYOCARDIAL INFARCTION MODEL

Myocardial infarction is a leading cause of death worldwide. Type-2 myocardial infarction is caused by non-atherothrombotic events leading to critical imbalance between oxygen supply and demand. Despite available treatments, mortality from the disease is much higher than in atherothrombosis-associated type-1 myocardial infarction. Therefore, better understanding of the underlying pathomechanism and identification of novel therapeutic targets are heavily needed. Many cellular functions damaged in the disease are regulated by signalling between the sarco/endoplasmic reticulum (SR/ER) and mitochondria. SR/ ER-mitochondria communication requires close physical contacts between the two organelles which is mediated by interaction between two molecular tethering proteins, the ER membrane protein vesicle-associated membrane protein-associated protein B (VAPB) and the outer mitochondrial membrane protein, protein tyrosine phosphatase interacting protein 51 (PTPIP51). However, despite the importance of SR/ER-mitochondria signalling, the exact local disease-associated changes in organelle tethering in the heart are not characterized. Here, we show, using a mouse isoprenaline induced type-2 myocardial infarction model and in situ proximity ligation assay that VAPB-PTPIP51 tethering is significantly increased in the heart of isoprenaline treated animals compared to the age matched control group. A key function of VAPB-PTPIP51 tethering is to promote calcium delivery from the SR/ER stores to mitochondria. This calcium communication involves in some extent the inositol 1,4,5-trisphosphate (IP3) receptor in the SR/ER and the voltage-dependent anion-selective channel (VDAC) in mitochondria. IP3 receptor and VDAC are closely coordinated in the opposing membranes, and we quantified their juxtaposition. We found that significantly more IP3 receptor is localised near VDAC in the isoprenaline treated than in the control group. Damages to SR/ER-mitochondria interaction may therefore contribute to pathological events in type-2 myocardial infarction and represent a potential new therapeutic target for the disease.