Discovery of a snail hibernation-inducer offering hibernation-like cardioprotection through metabolic rewiring and autophagy in mice

Hibernating animals achieve cellular dormancy through metabolic remodelling and autophagy, resisting ischemic and ischemia-reperfusion (IR) injury, while non-hibernators are vulnerable to both. Here we describe the discovery of a circulating dormancy-inducing factor in hibernating snails, which we synthesized chemically and because it activates PHLPP1 (a phosphatase regulating AKT and mTORC1/S6K1), named it SNail Activator of PHLPP1 (SNAP). During IR, plasma membrane PHLPP1 and p-AKT translocate to the cytoplasm and mitochondria, where SNAP dephosphorylates mitochondrial p-AKT and cytoplasmic p-S6K1, inducing dormancy in snails and promoting autophagy, reversible cell-cycle exit, proteostasis and apoptosis-resistance in IR-stressed mouse fibroblasts. In IR models of cardiomyocytes and perfused hearts, SNAP is cardioprotective by inducing autophagy, preserving Pyruvate Dehydrogenase (PDH) activity, preventing mitochondrial depolarization and ROS-induced ER stress. SNAP’s cardioprotective mitochondrial effects are absent in hearts with a cardiomyocyte-specific PDH knockout. SNAP reveals fundamental mechanisms of cellular stress protection and may be beneficial in the IR injury of normal hearts offered for transplantation, a major clinical challenge. Hibernating animals tolerate stress through an unknown mechanism that is absent in non-hibernators. Here, the authors show that a snail hibernation-inducing factor they discovered and synthesized, activates PHLPP1, offering cardioprotection in mice hearts through metabolic rewiring and autophagy