The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia

• Published in: Cell metabolism Vol. 27; no. 4; pp. 898 - 913.e7
• Main Authors: Sim, Jingwei, Cowburn, Andrew S., Palazon, Asis, Madhu, Basetti, Tyrakis, Petros A., Macías, David, Bargiela, David M., Pietsch, Sandra, Gralla, Michael, Evans, Colin E., Kittipassorn, Thaksaon, Chey, Yu C.J., Branco, Cristina M., Rundqvist, Helene, Peet, Daniel J., Johnson, Randall S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.04.2018; Cell Press
• Subjects: Adaptation, Physiological; Animals; Cell Hypoxia; Gene Expression Regulation; Glycolysis - physiology; HIF; hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Male; metabolism; Mice; Mice, Inbred C57BL; Mixed Function Oxygenases - metabolism; Oxygen - metabolism; Oxygen Consumption; Procollagen-Proline Dioxygenase - metabolism; Signal Transduction; Transcription, Genetic; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; HIF; hypoxia; metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.02.020

Animals require an immediate response to oxygen availability to allow rapid shifts between oxidative and glycolytic metabolism. These metabolic shifts are highly regulated by the HIF transcription factor. The factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that controls HIF transcriptional activity in an oxygen-dependent manner. We show here that FIH loss increases oxidative metabolism, while also increasing glycolytic capacity, and that this gives rise to an increase in oxygen consumption. We further show that the loss of FIH acts to accelerate the cellular metabolic response to hypoxia. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues: we analyzed skeletal muscle FIH mutants and found a decreased metabolic efficiency, correlated with an increased oxidative rate and an increased rate of hypoxic response. We find that FIH, through its regulation of oxidation, acts in concert with the PHD/vHL pathway to accelerate HIF-mediated metabolic responses to hypoxia. [Display omitted] •FIH loss increases oxidative metabolism, while also increasing glycolytic capacity•This accelerates the hypoxic response, ultimately suppressing oxidative metabolism•FIH acts in concert with PHD/vHL to accelerate HIF-mediated responses to hypoxia•This rapid adaption serves tissues with high levels of oxygen flux, such as muscle Cells transition between aerobic and anaerobic metabolism when adapting to changes in oxygen supply. Sim et al. find that the enzyme FIH is expressed at high levels in skeletal muscle and decreases in activity under hypoxia. With the loss of FIH, cells have increased aerobic metabolism, which paradoxically accelerates other adaptations to hypoxia.