Hippocampal TRAP1 overexpression mitigates hypoxia-evoked learning and memory impairments via MERCS

Chronic exposure to high-altitude hypoxia impairs hippocampus-dependent learning and memory. However, the upstream mitochondrial mechanisms by which oxygen deficiency triggers synaptic dysfunction remain incompletely understood. Therefore, the present study aimed to investigate the role of tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondria-restricted chaperone, in this pathological process. In vivo, adult male Sprague-Dawley rats were exposed to a hypobaric chamber simulating an altitude of 5,000 m for 28 days. In vitro, HT22 hippocampal neurons were exposed to 1% oxygen (O₂) for 48 h to establish hypoxic cell models. TRAP1 was overexpressed using lentivirus or pharmacologically activated by a selective WNT5a agonist. Hippocampal structure and cognition were evaluated. MERCS, intracellular calcium (Ca²⁺) and reactive oxygen species (ROS), mitochondrial DNA (mtDNA) integrity and gene expression quantification, synaptic-related proteins and their interactions were examed. Hypoxia led to a significant downregulation of hippocampal TRAP1 and WNT5a expression. It caused a reduction in MERCS, mtDNA and the expression of brain-derived neurotrophic factor, doublecortin, and postsynaptic density protein 95. Increased the mitochondrial ROS and mitochondrial Ca²⁺ concentration. Notably, Trap1 overexpression reversed these hypoxia-induced deficits. Trap1 knockdown recapitulated the hypoxic injury phenotypes. Additionally, treatment with a WNT5a agonist upregulated TRAP1, inhibited dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, and exerted a neuroprotective effect against hypoxia-induced neuronal damage. TRAP1 downregulation is an early and reversible event that links hypoxic stress to mitochondria, ER dysfunction and cognitive impairment. Direct Trap1 overexpression or indirect upregulation via WNT5a agonism represents a promising dual therapeutic strategy for hypoxia-induced neurodegeneration and memory deficits.