PERK's novel agonist protects against myocardial ischemia-reperfusion injury by modulating ER-mitochondria contacts and phosphatidic acid transport

The role of PERK in maintaining the homeostasis of mitochondria-associated membrane (MAM) is believed to exert a significant impact on mitochondrial energy metabolism and structural morphology. However, there exists controversy regarding the therapeutic effect of PERK activation on ischemia-reperfusion injury. We have discovered a novel agonist for PERK named ZY341. ZY341 interacts with the active pocket of PERK through π-π stacking interaction, and surface plasmon resonance experiments have confirmed its exceptional affinity as an agonist with a Kd value of 17.5 μM. This study provides initial evidence that ZY341 exhibits potent activity as a PERK agonist, effectively activating the PERK/eIF2α pathway in a mouse model of ischemia-reperfusion and demonstrating significant anti-apoptotic effects on cardiomyocytes. Ischemia-reperfusion not only induces cardiomyocyte apoptosis but also leads to substantial increases in MAM-mediated mitochondrial calcium overload, resulting in severe damage to mitochondrial structure and function. ZY341 significantly protects cardiac myocytes' respiratory capacity and improves heart function. Mechanistically, through PERK activation, ZY341 inhibits abnormal binding between VAPB-PTPIP51 complex in OGD/R models, regulates MAM-mediated calcium ion and phosphatidic acid transport homeostasis, suppresses mitochondrial fragmentation thereby significantly enhancing cardiac function. In conclusion, this study unveils new avenues for targeting PERK as a therapeutic strategy for myocardial ischemia-reperfusion treatment.