HPC restores mitochondrial homeostasis and ameliorates hypoxic stress through the GSK-3β/β-catenin signaling pathway

Hypoxic preconditioning (HPC) can increase the hypoxia tolerance of the mouse hippocampus both in vivo and in vitro by upregulating ATP levels, which may depend on mitochondrial homeostasis. The GSK-3β/β-catenin signaling pathway is involved in neuroprotection after brain ischemia. The aim of this study was to explore whether HPC can activate GSK-3β/β-catenin to improve the hypoxia tolerance of neuronal cells by enhancing mitochondrial homeostasis. In vitro and in vivo analyses revealed that HPC upregulates the activity of the GSK-3β/β-catenin pathway, maintaining mitochondrial morphological stability. Mechanistically, GSK-3β activity is negatively correlated with mitochondrial homeostasis. Pharmacological inhibition of GSK-3β reduced mitochondrial fission, whereas HPC suppressed GSK-3β expression to attenuate fission and preserve mitochondrial integrity. Conversely, GSK-3β overexpression abrogated HPC-mediated protection and exacerbated mitochondrial dysfunction. These findings elucidate a neuroprotective mechanism whereby HPC stabilizes mitochondrial dynamics via modulation of the GSK-3β/β-catenin pathway, providing novel experimental insights into HPC-mediated neuroprotection.