The Neuroprotective Mechanism of Hypoxic Adaptation in Brandt’s Vole: Roles of PDK1 and Metabolic Reprogramming

Oxygen is indispensable for aerobic life, and its deprivation poses a critical threat to survival, particularly in highly metabolically active tissues such as the brain. Brandt’s voles ( Lasiopodomys brandtii ), which inhabit structurally complex burrow systems with a naturally hypoxic environment, have developed remarkable hypoxia tolerance through long-term ecological adaptation. Compared to conventional laboratory mice, Brandt’s voles maintain cognitive function following acute hypoxia (7.5% O₂, 6 h), whereas mice exhibit significant cognitive impairment under the same conditions. However, the underlying neuroprotective mechanisms remain poorly understood. Here, we subjected Brandt’s voles to chronic (10% O₂, 48 h) and intermittent hypoxia (10% O₂, 6 h/day for 7 days) to investigate the molecular and cellular basis of their adaptive resilience. Integrated transcriptomic analysis revealed that pyruvate dehydrogenase kinase 1 (PDK1) was significantly upregulated in the brains of hypoxia-exposed Brandt’s voles. Functional validation in HT22 hippocampal neurons demonstrated that overexpression of Brandt’s vole-derived PDK1 conferred superior protection against hypoxic injury compared to its mouse ortholog, as evidenced by enhanced cell viability, migration, proliferation, and wound healing, alongside a more pronounced reduction in apoptosis. Metabolic assays further revealed concomitant shifts in lactate, pyruvate, and ATP levels, suggesting that PDK1 mediates neuroprotection through metabolic reprogramming, potentially by modulating the tricarboxylic acid cycle and promoting a glycolytic shift. Collectively, our findings establish PDK1 as a critical effector of hypoxia tolerance in Brandt’s voles and highlight the enhanced neuroprotective potency of the vole-specific PDK1 variant. This study uncovers a novel endogenous adaptive strategy with promising translational implications for treating hypoxia-related neurological disorders.