Exploring the molecular interface between the HIF/hypoxia signalling pathway and mitochondria in cancer

大多数生物体需要氧气才能生存并有效地产生能量。线粒体是重要的亚细胞区室，存在于所有动物细胞中，消耗氧气并产生化学能。当细胞中的氧含量发生变化时，一种叫做hif -1 α的“氧传感器”就会增加，并开启细胞核中的特定基因。我们发现了一种人类基因（CHCHD4），它编码两种与hif -1 α相互作用的线粒体蛋白。此外，我们还发现hif -1 α蛋白在细胞中定位于线粒体。我们之前已经证明，当细胞经历低氧水平（缺氧）时，CHCHD4蛋白对于调节细胞中可用的hif -1 α蛋白的数量是必不可少的。这一点很重要，因为高水平的hif -1 α与多种人类疾病有关，包括心脏和肾脏疾病、中风和癌症，其中缺氧是导致疾病病理和严重程度的关键因素。hif -1 α蛋白与线粒体定位和与CHCHD4蛋白结合的作用尚不清楚。因此，本研究将探索hif -1 α和线粒体之间的分子界面，并特别关注hif - α:CHCHD4相互作用在调节肿瘤细胞线粒体功能和代谢中的作用。这项工作将帮助我们确定肿瘤细胞如何适应其缺氧微环境的新机制。

Most organisms need oxygen to survive and generate energy efficiently. Mitochondria are essential subcellular compartments, present within all animal cells that consume oxygen and generate chemical energy. When cellular oxygen levels change, an "oxygen-sensor" called HIF-1alpha increases and switches on specific genes in the nucleus. We have discovered a human gene (CHCHD4) that encodes two mitochondrial proteins that interact with HIF-1alpha. Furthermore, we have also found that HIF-1alpha protein localizes with mitochondria in cells. We have previously shown that CHCHD4 proteins are essential for regulating the amount of HIF-1alpha protein available in the cell when cells experience low oxygen levels (hypoxia). This is important, because high levels of HIF-1alpha are associated with several human diseases including heart and kidney disease, stroke and cancer, where hypoxia is a key contributing factor to the pathology and severity of the disease. The role of HIF-1alpha protein localization with mitochondria and binding to CHCHD4 protein is not known. Thus, the proposed work will explore the molecular interface between HIF-1alpha and mitochondria with specific focus on the role of the HIF-alpha:CHCHD4 interaction in regulating mitochondrial function and metabolism in tumour cells. This work will help us identify novel mechanisms for how tumour cells adapt to their hypoxia microenvironment.