ULK1-linked mitophagy promotes cardiac hypoxia tolerance in the blind mole-rat

Abstract Blind mole-rats (BMRs) thrive in chronically hypoxic subterranean environments, displaying exceptional cardiac resilience to conditions that rapidly induce failure in other mammals. Here, we integrate in vivo physiology, multi-omics profiling, mitochondrial analyses, and genome editing to uncover an evolved cardioprotective program in BMRs. Under acute 0% O₂ exposure, BMRs exhibit markedly prolonged survival compared to mouse. At the molecular level, BMR hearts undergo coordinated metabolic remodeling, restrained inflammatory signaling, and enhanced genome maintenance. Functionally, BMR cardiac mitochondria suppress high-flux oxidative phosphorylation and reverse electron transport–associated ROS following hypoxia, indicating intrinsic adaptation to oxygen collapse. Hypoxia selectively activates AMPK–mTOR(definition)–ULK1 dependent mitophagy, and pharmacological manipulation demonstrates that mitophagy is required for BMR cardiomyocyte survival during hypoxia-reoxygenation stress. Finally, we identify a BMR-specific insertion in ULK1 and demonstrate that introduction of this sequence into rat cardiomyocytes enhances hypoxia tolerance in a mitophagy-dependent manner. These findings reveal an evolutionarily tuned mitochondrial quality-control strategy that enables extreme cardiac resilience to hypoxia.