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Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrels

Many organisms, from anaerobic bacteria to hibernating ground squirrels, have evolved mechanisms to tolerate severe hypoxia or ischemia. In particular, the arctic ground squirrel (AGS) has been shown to be highly resilient to ischemic and reperfusion injuries, demonstrating an ability to withstand metabolic stress under hibernation conditions. Although physiological adaptations are critical to ischemic tolerance in AGS, little is known about cellular mechanisms underlying intrinsic AGS cell tolerance to metabolic stressors. Through cell survival-based cDNA expression screens and comparative genomics, we have discovered that in AGS, a cytoprotective variant of ATP5G1 helps confer improved mitochondrial metabolism and cell resilience to metabolic stress. ATP5G1 encodes a proton-transporting subunit of the mitochondrial ATP synthase complex. Ectopic expression in mouse cells and CRISPR/Cas9 base editing of the endogenous AGS locus revealed causal roles of one AGS-specific amino acid substitution (leucine-32) in mediating the cytoprotective effects of AGS ATP5G1. We provide evidence that AGS ATP5G1 promotes cell resilience to stress by modulating mitochondrial morphological change and metabolic functions. Thus, our results identify a naturally occurring variant of ATP5G1 from a mammalian hibernator that causally contributes to intrinsic cytoprotection against metabolic stresses.