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

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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.