Abstract
Many organisms in nature have evolved mechanisms to tolerate severe hypoxia or ischemia, including the hibernation-capable Arctic ground squirrel (AGS). Although hypoxic or ischemia tolerance in AGS involves physiological adaptations, little is known about the critical cellular mechanisms underlying intrinsic AGS cell resilience to metabolic stress. Through cell survival-based cDNA expression screens in neural progenitor cells, we identify a genetic variant of AGS Atp5g1 that confers cell resilience to metabolic stress. Atp5g1 encodes a subunit of the mitochondrial ATP synthase. Ectopic expression in mouse cells and CRISPR/Cas9 base editing of endogenous AGS loci revealed causal roles of one AGS-specific amino acid substitution in mediating cytoprotection by AGS ATP5G1. AGS ATP5G1 promotes metabolic stress resilience by modulating mitochondrial morphological change and metabolic functions. Our results identify a naturally occurring variant of ATP5G1 from a mammalian hibernator that critically contributes to intrinsic cytoprotection against metabolic stress.
Highlights
Arctic ground squirrels (AGS, Urocitellus parryii) survive harsh winter environmental conditions through hibernation
Using a cDNA library expression-based genetic screen combined with phenotypic analyses of cell survival and mitochondrial responses to stress as compared in mouse versus AGS neural progenitor cells (NPCs), we identified AGS transcripts imparting ex vivo cytoprotection against various metabolic stressors
(1% O2), hypothermia (31 ̊C), or rotenone (30 mM), AGS NPCs exhibit profound resistance to cell death compared with mouse NPCs (Figure 1C), recapitulating resilient AGS phenotypes found in previous studies (Dave et al, 2009; Bhowmick et al, 2017; Bogren et al, 2014; Drew et al, 2016)
Summary
Arctic ground squirrels (AGS, Urocitellus parryii) survive harsh winter environmental conditions through hibernation. Hibernating ground squirrels are resistant to ischemic and reperfusion injuries in numerous models, including brain and heart tissues after cardiac arrest in vivo and hippocampal slice models derived from animals during an IBA (Dave et al, 2009; Quinones et al, 2016; Bhowmick et al, 2017; Bogren et al, 2014). This resilience to reperfusion injury does not depend on temperature of the animal or season (Bhowmick et al, 2017). These studies suggest that in addition to physiological adaptations, AGS possess cell autonomous genetic mechanisms that contribute to intrinsic tolerance to metabolic stress or injury
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