Mitochondria and Hypoxia Signalling

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• Professor Margaret Ashcroft | Dept. of Medicine, University of Cambridge
• Tuesday 11 June 2019, 15:00-16:00
• Sackler Lecture Theatre (Level 7) The Keith Peters Building, Cambridge Biomedical Campus.

If you have a question about this talk, please contact Hannah Burns.

Metabolic reprogramming and mitochondrial metabolism is a hallmark of cancer. Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive and thus mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, given the importance of mitochondrial function for normal physiological processes, delineating how mitochondrial OXPHOS underlies tumorigenesis is crucial for understanding the potential therapeutic benefit of exploiting mitochondrial metabolism in cancer.

When considering the metabolic landscape of tumours, while tumour origin, genetic background and heterogeneity contribute to a diverse metabolic environment across tumours, the central unifying metabolic stimulus in tumours is hypoxia (low oxygenation). Hypoxia is a key feature of the tumour microenvironment, and presents a major clinical and therapeutic challenge as it enables tumours to survive, metastasize and resist killing by front-line treatments. My group has long-standing expertise in hypoxia signalling, and important advances to our understanding of the key transcriptional drivers involved in hypoxia signalling such as hypoxia inducible factor (HIF), have enabled us to identify and develop novel small molecule HIF signalling inhibitors.

Hypoxia and HIF activation, as well as oncogenic and proliferative signals are known to drive metabolic adaptive responses primarily through transcriptional (and epigenetic) re-programming that in part promote a shift in fuel utilization, resulting in dynamic changes in glycolysis and OXPHOS . Alterations in mitochondrial metabolism are not only a downstream consequence of HIF activation, but mitochondria as the cellular sites for oxygen consumption, regulate hypoxia (and HIF ) signalling through multiple means, including basal oxygen consumption rate (OCR), metabolic intermediates and reactive oxygen species (ROS) generation. But how do tumours dial up their mitochondria to fuel their metabolic demands when oxygen is limiting? Other than HIF itself, the key molecular mechanisms controlling intracellular oxygenation and hypoxia signalling that contribute to tumorigenesis through control of tumour metabolic adaptive responses and tumour cell survival/growth are not understood.

Thus, we have been investigating the cross-talk between mitochondria and hypoxia (and HIF ) signalling. Previously, we discovered the redox-sensitive mitochondrial import protein, coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) is critical for controlling intracellular oxygenation, hypoxia signalling and metabolism in tumour cells. We have shown that CHCHD4 (also known as MIA40 ) is required for tumour growth in vivo, and is an essential gene in cancer irrespective of aetiology. CHCHD4 provides an import and oxidoreductase-mediated protein folding function along with the sulfhydryl oxidase GFER (ALR/Erv1) as a key component of the mitochondrial disulfide relay system (DRS) within the intermembrane space (IMS). In this way, CHCHD4 participates in electron transfer to complex IV (CIV), the molecular oxygen acceptor of the respiratory chain. Overexpression of CHCHD4 in a range of human cancers correlates with increased tumour progression, disease recurrence and poor patient survival, and provides a proliferative and metabolic advantage to tumour cells in both normoxia and hypoxia. Using our novel small molecule HIF inhibitors, genome-wide CRISPR /Cas9 deletion screening, global proteomic and SILAC analyses, as well as a range of unique cell and model systems that we have generated, we have been investigating how the CHCHD4 -HIF axis works, and how the CHCHD4 -HIF axis contributes to tumorigenesis.

This talk is part of the MRC Mitochondrial Biology Unit Seminars series.

This talk is included in these lists:

• All Talks (aka the CURE list)
• CamBridgeSens
• Cambridge talks
• Life Science Interface Seminars
• MRC Mitochondrial Biology Unit Seminars
• Sackler Lecture Theatre (Level 7) The Keith Peters Building, Cambridge Biomedical Campus
• Trust & Technology Initiative - interesting events

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