Deletion of the foxO4 Gene Increases Hypoxia Tolerance in Zebrafish

Oxygen homeostasis is an important organizing principle for understanding development, physiology, disease, and evolution. Under various physiological and pathological states, organisms experience oxygen deficiency or hypoxia. FoxO4 has been recognized as an important transcriptional regulator involved in a variety of cellular functions, including proliferation, apoptosis, differentiation, and stress resistance, but its role in hypoxia adaptation mechanisms in animals is not so clear. To explore the role of foxO4 in the hypoxia response, we detected the expression of foxO4 and the regulatory relationship between Hif1α and foxO4 under hypoxic conditions. It was found that the expression of foxO4 was up-regulated in ZF4 cells and zebrafish tissues after hypoxia treatment, and Hif1α could directly target the HRE of the foxO4 promoter to regulate foxO4 transcription, indicating that foxO4 was involved in the hypoxia response by the Hif1α-mediated pathway. Furthermore, we obtained foxO4 knockout zebrafish and found that the disruption of foxO4 increased the tolerance to hypoxia. Further research found that the oxygen consumption and locomotor activity of foxO4^-/- zebrafish were lower than those of WT zebrafish, as was true for NADH content, NADH/NAD⁺ rate, and expression of mitochondrial respiratory chain complex-related genes. This suggests that disruption of foxO4 reduced the oxygen demand threshold of the organism, which explained why the foxO4 zebrafish were more tolerant to hypoxia than WT zebrafish. These results will provide a theoretical basis for further study of the role of foxO4 in the hypoxia response.