Keratinocyte Mitochondria as a Systemic Oxygen Sensors

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The major function of mitochondria in cellular homeostasis has historically been the generation of energy through oxidative phosphorylation. However, we and others have demonstrated that mitochondria can serve as a signaling organelle. The projects described in my lab are driven by the hypothesis that when cells encounter stress the mitochondria serve as key regulators of biological outcomes that include the induction of adaptive genes, cellular proliferation, senescence and death. One stress we study is how cells respond to decreased oxygen levels (hypoxia). Multi-cellular organisms have evolved multiple mechanisms to respond to hypoxia. Healthy individuals typically encounter hypoxia at high altitudes, where at least three prominent physiological responses take place: neurotransmitter release by the carotid body to increase breathing; pulmonary vascular constriction to shunt blood to better oxygenated regions of the lung; and production of the hormone erythropoietin (EPO) in the liver to enhance red blood cell mass and hemoglobin concentration in the blood. At the molecular level the physiological responses to hypoxia are mediated by the transcription factor hypoxia inducible factor, H1F-1. A recent study demonstrated that when mice with a keratinocyte-specific deletion of HIF-1 were exposed to hypoxia, the predicted increase in plasma EPO levels was blunted and induction of EPO expression in the kidney was lost. This was surprising because it suggested that the keratinocytes were sensing the hypoxia to activate HIF-1 and regulate EPO production in the kidney. But how cells sense decreases in oxygen to activate HIF dependent gene expression is not fully understood. We will test whether mitochondria function as oxygen sensors in the keratinocytes to induce HIF-1 to regulate EPO production in mice.