Cold-shock response and metabolic rewiring drive cardiac reversibility in hypothermia

Background

Accidental hypothermia can exhibit unexpected cardiac reversibility, including recovery after prolonged resuscitation. The cold-specific molecular programs that may support this reversibility remain poorly defined. We sought to define metabolic and ultrastructural cardiac remodeling induced by hypothermia and to identify transcriptional programs associated with survival and recovery.

Methods and Results

Mice were fasted and exposed to 4°C for 6 or 12 hours; fasted room temperature served as control. Metabolomic profiling of cardiac lysates demonstrated a hypothermia-associated metabolic signature characterized by depletion of α-ketoglutarate and accumulation of 2-hydroxyglutarate (2HG), accompanied by reduced ATP levels, consistent with suppressed oxidative metabolism. Histopathology at 12 hours revealed focal contraction band–like changes. Transmission electron microscopy showed prominent ultrastructural remodeling, including disruption of actomyosin bundles and accumulation/redistribution of mitochondria within widened myofibrillar spaces. Increased mitochondrial DNA content supported altered mitochondrial abundance. Notably, despite these injury-like features at the hypothermic time point, rewarming followed by 24 hours of recovery resulted in near-complete resolution of contraction band–like histology, with only small residual lipid droplets detectable by electron microscopy, indicating substantial structural reversibility.

To characterize survival-associated transcriptional responses during hypothermia, we performed RNA sequencing at 12 hours. Transcriptomic analysis revealed robust induction of pro-survival gene programs, highlighted by marked upregulation of MYC and CDKN1A (p21). These changes suggest activation of an adaptive response that coordinates metabolic rewiring with transcriptional control of stress tolerance and checkpoint regulation, potentially enabling recovery upon rewarming.

Conclusion

Hypothermia induces a distinctive and largely reversible cardiac phenotype featuring α-ketoglutarate depletion, 2HG accumulation, reduced energetic status, and dynamic mitochondrial remodeling. Concomitant activation of MYC and p21–associated survival/checkpoint programs supports the concept of a cold-specific mitochondria–metabolism–gene regulation axis that may underlie the clinical reversibility observed in hypothermic cardiac arrest and highlights candidate pathways for therapeutic modulation during rewarming and resuscitation.