Mitochondrial Ucp4 Ameliorates Motor Disorders by Protecting Cerebellar Purkinje Cells from Oxidative Stress in Intermittent Hypobaric Hypoxia Mice

Acute altitude hypoxia is a syndrome that manifests at elevations exceeding 2500 m, posing significant health challenges to individuals who travel or work at high altitudes. Uncoupling proteins are integral proteins located within the mitochondrial inner membrane, playing a crucial role in modulating proton leakage across the mitochondrial membrane. This study investigates the potential role of uncoupling protein 4 (Ucp4) overexpression in an intermittent hypobaric hypoxia (IHH) model and its underlying mechanisms in the cerebellar dyskinesia phenotype. An IHH model was developed using a low-pressure hypoxic chamber, exposing mice to 16 h of hypoxia daily for 5 days. Three mouse strains were used: C57BL/6J, Pcp2Cre; Ucp4fl/fl, and Pcp2Cre; Mito-GFP. Behavioral tests, including rotarod, open field, balance beam, and Morris water maze, were conducted. Ucp4-overexpressing virus was administered to cerebellar lobes 4/5. Mitochondrial morphology was assessed via transmission electron microscopy, 3D reconstruction, and network analysis, while function was evaluated through reactive oxygen species, mitochondrial membrane potential (MMP), glutathione/glutathione disulfide ratio, adenosine triphosphate levels, qPCR, and Western blotting. Results showed that IHH induces hypoactivity without affecting spatial cognition. IHH-induced hypoactivity is linked to Ucp4 upregulation and increased mitochondrial fragmentation in Purkinje cells (PCs), though overall mitochondrial dynamics remain balanced. Ucp4 deficiency exacerbates IHH-induced hypoactivity and mitochondrial fragmentation. Conversely, Ucp4 overexpression in PCs significantly alleviates these effects. Mechanistically, Ucp4 protects PCs by stabilizing MMP and regulating oxidative stress, maintaining mitochondrial integrity. This study reveals that Ucp4 protects cerebellar PCs from oxidative stress in IHH, improving motor function and identifying Ucp4 as a potential therapeutic target for intermittent high-altitude syndrome. Antioxid. Redox Signal. 00, 000-000.