Specific cyprinid HIF isoforms contribute to cellular mitochondrial regulation

Hypoxia-inducible factor 1 (HIF-1) functions as a master regulator of the cellular response to hypoxic stress. Two HIF-1α paralogs, HIF-1αA and HIF-1αB, were generated in euteleosts by the specific, third round of genome duplication, but one paralog was later lost in most families with the exception of cyprinid fish. How these duplicates function in mitochondrial regulation and whether their preservation contributes to the hypoxia tolerance demonstrated by cyprinid fish in freshwater environments is not clear. Here we demonstrated the divergent function of these two zebrafish Hif-1a paralogs through cellular approaches. The results showed that Hif-1aa played a role in tricarboxylic acid cycle by increasing the expression of Citrate synthase and the activity of mitochondrial complex II, and it also enhanced mitochondrial membrane potential and ROS production by reducing free Ca(2+) in the cytosol. Hif-1ab promoted intracellular ATP content by up-regulating the activity of mitochondrial complexes I, III and IV and the expression of related genes. Furthermore, both the two zebrafish Hif-1a paralogs promoted mitochondrial mass and the expression level of mtDNA, contributing to mitochondrial biogenesis. Our study reveals the divergent functions of Hif-1aa and Hif-1ab in cellular mitochondrial regulation.