Keratinocyte Mitochondria as a Systemic Oxygen Sensors

线粒体在细胞内稳态中的主要功能历来是产生能量 通过氧化磷酸化然而，我们和其他人已经证明，线粒体可以作为 一种信号细胞器在我的实验室中描述的项目是由一个假设驱动的，即当细胞遇到 线粒体作为生物学结果的关键调节器，包括诱导适应性 基因、细胞增殖、衰老和死亡。我们研究的一种压力是细胞如何应对 氧水平（缺氧）。多细胞生物已经进化出多种机制来应对缺氧。 健康的个体通常在高海拔地区遇到缺氧，在那里至少有三个突出的生理 反应发生：神经递质释放的颈动脉体，以增加呼吸;肺血管 收缩以将血液分流到肺部更好的氧合区域;以及激素的产生 促红细胞生成素（EPO）在肝脏中的作用，以提高血液中的红细胞质量和血红蛋白浓度。在 在分子水平上，缺氧的生理反应是由缺氧转录因子介导的 诱导因子H1 F-1。最近的一项研究表明，当小鼠具有角质细胞特异性缺失时， HIF-1暴露于缺氧，预期的血浆EPO水平的增加被钝化， 肾脏中的表达丧失。这是令人惊讶的，因为它表明角质形成细胞感觉到 低氧激活HIF-1和调节EPO在肾脏中的产生。但是细胞的感知能力会降低， 氧激活HIF依赖性基因表达的机制还不完全清楚。我们将测试线粒体 作为角化细胞中的氧传感器，诱导HIF-1调节小鼠中EPO的产生。

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.