Mitochondrial Mechanisms Of Resilience Revealed By Arctic Ground Squirrel Neural Cells

Arctic ground squirrels (AGS) are extreme hibernators capable of withstanding months of freezing temperatures. Curiously, AGS do not experience ischemic or reperfusion injuries despite limited cardiac output and cerebral blood flow during hibernation. Indeed, in simulated stroke or cardiac arrest, AGS also demonstrate marked resilience independent of the season or metabolic state of the animal. We found that AGS neuronal stem and progenitor cells (NSC/NPCs) demonstrate dramatic tolerance to multiple mitochondrial insults including oxygen glucose deprivation, rotenone treatment (Complex I inhibition), or FCCP treatment (uncoupling agent) in vitro. We sought to characterize the mitochondrial adaptations mediating this resilient phenotype. The AGS resilient phenotype is associated with altered mitochondrial dynamic regulation of fusion/fission and reduced oxidative metabolism. Overexpression of key AGS nuclear-encoded mitochondrial subunits such as Cox7a2l in mouse NSC/NPCs recapitulated the resilient phenotype and mitochondrial morphological and functional changes. AGS mitochondrial proteins are uniquely adapted to withstand metabolic stressors and contribute to the ability of AGS to dynamically regulate mitochondrial function. Development of therapeutic agents targeting mitochondrial structural properties may induce a protective phenotype and promote neuronal survival in patients with acute stroke.