An inducer of snail hibernation causes quiescence and hibernation-like cardioprotection, through metabolic rewiring and autophagy, in mice hearts
Piao, J.; Zhang, Y.; Zhao, Y.-Y.; Hanington, P.; Hambrook, J. R.; Liu, Y.; Ussher, J.; Dakhili, A. T.; Sutendra, G.; Michelakis, E. D.
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Cells of hibernators achieve dormancy, resembling cellular quiescence, through molecular rewiring, metabolic remodelling and autophagy, resisting ischemic and ischemia-reperfusion (IR) injury, while non-hibernators are vulnerable to both. We discovered a circulating dormancy-inducing factor in hibernating snails, synthesized it chemically and because it activates PHLPP1 (a phosphatase regulating the mTOR mediators p-AKT and p-S6K1), named it SNail Activator of PHLPP1 (SNAP). During IR, plasma membrane PHLPP1 and p-AKT translocate to the cytoplasm and mitochondria. SNAP dephosphorylates mitochondrial p-AKT, p-S6K1 and induces dormancy in snails and quiescence (autophagy, reversible cell-cycle exit, proteostasis, apoptosis-resistance) in ischemic mouse fibroblasts. In IR models of cardiomyocytes and perfused hearts, SNAP is cardioprotective by preserving Pyruvate Dehydrogenase (PDH) activity, preventing mitochondrial depolarization, apoptosis and ROS-induced ER stress. SNAPs cardioprotective and mitochondrial effects are absent in hearts with a cardiomyocyte-specific PDH knockout. SNAP reveals fundamental mechanisms of quiescence under stress; while its cardioprotection may be beneficial in the IR injury of normal hearts offered for transplantation, a major challenge in transplant medicine.
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