Hypoxia-inducible factor-1α shifts metabolism from oxidative phosphorylation to glycolysis in response to pathogen challenge in Apostichopus japonicus

Abstract The immune system requires a considerable energetic cost to sense and respond to pathogen invasion. The metabolic reprogramming of the immune cells has been proved to meet the energetic demands and drive the secretion of cytokines and inflammatory mediators. However, the shift of energy metabolic pathways in response to pathogen challenge in marine invertebrates is still lacking in understanding. In this study, we detected the changes of four metabolites (ATP, lactate, ROS, and NO), vitality of two metabolic enzymes (PK and SDH), transcripts of four key genes related to the glucose metabolic pathway (GLUT1, PDK1, LDHA, PDH), as well as coelomocyte proliferation rate in pathogen-challenged Apostichopus japonicus. We discovered that glycolysis was significantly induced, whereas oxidative phosphorylation (OXPHOS) was depressed in response to pathogen infection. These phenomena suggested that metabolic switch occurs when immune cells are activated. To determine the underlying regulatory mechanism behind these changes, we cloned and characterized AjHIF-1α and found that AjHIF-1α was significantly induced and can be transferred into the nucleus after LPS exposure. After AjHIF-1α inhibition, the expression levels of the its downstream genes including GLUT1, LDHA, and PDK1 and the contents of glycolytic products ATP, lactate, and ROS were both reduced. Meanwhile, the expression levels of key metabolic enzyme PDH in OXPHOS was increased after AjHIF-1α inhibition. Furthermore, the inhibition of AjHIF-1α-mediated glycolysis could reduce coelomocyte survival rate and promote coelomocyte mortality rate. These results collectively revealed that AjHIF-1α is involved in immune regulation as a switch from OXPHOS to glycolysis.