Non-canonical Function of a Hif-1α Splice Variant Contributes to the Sustained Flight of Locusts

The hypoxia inducible factor (Hif) pathway is functionally conserved across metazoans in modulating cellular adaptations to hypoxia. However, the functions of this pathway under aerobic physiological conditions are rarely investigated. Here, we show that Hif-12, a locust Hif-1 isoform, does not induce canonical hypoxic responses but functions as a specific regulator of locust flight, which is a completely aerobic physiological process. Two Hif-1 splice variants were identified in locusts, a ubiquitously expressed Hif-11 and a muscle-predominantly expressed Hif-12. Hif-11 that induces typical hypoxic responses upon hypoxia exposure, remains inactive during flight. By contrast, the expression of Hif-12, which lacks C-terminal transactivation domain, is less sensitive to oxygen-tension but induced extensively by flying. Hif-12 sustains flight endurance by promoting glucose oxidation while simultaneously maintaining redox homeostasis by upregulating the production of a reactive oxygen species (ROS) quencher, DJ-1. Overall, this study reveals a novel Hif-mediated mechanism underlying prolonged aerobic physiological activity.