Inter-connection between mitochondria and HIFs

Introduction Oxidative phosphorylation Hypoxic activation of HIFs Mitochondria regulate HIFs Mitochondrial ROS regulate HIFs Mitochondrial respiration regulate HIFs TCA cycle intermediates regulate HIFs Hypoxia decreases cellular ATP utilization to diminish mitochondrial respiration HIF-1 regulates mitochondrial respiration HIF-2 regulates mitochondrial oxidative stress Conclusion The transcription factors hypoxia inducible factors 1 and 2 (HIF-1 and HIF-2) regulate multiple responses to physiological hypoxia such as transcription of the hormone erythropoietin to enhance red blood cell proliferation, vascular endothelial growth factor to promote angiogenesis and glycolytic enzymes to increase glycolysis. Recent studies indicate that HIFs also regulate mitochondrial respiration and mitochondrial oxidative stress. Interestingly, mitochondrial metabolism, respiration and oxidative stress also regulate activation of HIFs. In this review, we examine the evidence that mitochondria and HIFs are intimately connected to regulate each other resulting in appropriate responses to hypoxia.