Cytochrome c oxidase subunit I (COX1) protects against hypoxic-ischemic injury in HT22 neurons by inhibiting oxidative stress and apoptosis through the Nrf2/HO-1 signaling.
Abstract
UNLABELLED: Hypoxic-ischemic encephalopathy (HIE) is characterized by mitochondrial dysfunction, excessive oxidative stress, and neuronal apoptosis. Cytochrome c oxidase subunit I (COX1), the catalytic core subunit of mitochondrial complex IV, is particularly susceptible to reactive oxygen species-mediated damage and may influence neuronal survival under hypoxic-ischemic conditions. However, the role of COX1 in HIE and its underlying mechanisms remain unclear. HIE related genes were screened by intergrating data from the GEOGSE144456 and GSE112137 datasets . An oxygen-glucose deprivation (OGD) injury model was established in HT22 cells. COX1 expression was quantified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Cell viability, proliferation, and apoptosis were assessed using Cell Counting Kit-8 (CCK-8) assays, 5-ethynyl-2'-deoxyuridine (EdU) assays, and annexin V/propidium iodide flow cytometry, respectively. Bioinformatic analysis identified COX1 as a candidate HIE-related target. OGD markedly reduced COX1 expression in HT22 cells. COX1 overexpression increased cell viability and proliferation, reduced apoptosis and cleaved caspase-3 expression, decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, increased glutathione (GSH) content and superoxide dismutase (SOD) activity, and upregulated nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. These effects were attenuated by the Nrf2 inhibitor ML385. COX1 may protect against oxygen-glucose deprivation-induced neuronal injury by activating the Nrf2/HO-1 pathway, reducing oxidative stress, and suppressing apoptosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s10616-026-01105-5.
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