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SUMMARY:Mitochondria and Hypoxia Signalling - Professor Margaret Ashcroft 
 | Dept. of Medicine\, University of Cambridge
DTSTART:20190611T140000Z
DTEND:20190611T150000Z
UID:TALK125896@talks.cam.ac.uk
CONTACT:Hannah Burns
DESCRIPTION:Metabolic reprogramming and mitochondrial metabolism is a hall
 mark of cancer. Tumour cells rely on glycolysis and mitochondrial oxidativ
 e phosphorylation (OXPHOS) to survive and thus mitochondrial OXPHOS has be
 come an increasingly attractive area for therapeutic exploitation in cance
 r. However\, given the importance of mitochondrial function for normal phy
 siological processes\, delineating how mitochondrial OXPHOS underlies tumo
 rigenesis is crucial for understanding the potential therapeutic benefit o
 f exploiting mitochondrial metabolism in cancer.  \n\nWhen considering the
  metabolic landscape of tumours\, while tumour origin\, genetic background
  and heterogeneity contribute to a diverse metabolic environment across tu
 mours\, the central unifying metabolic stimulus in tumours is hypoxia (low
  oxygenation). Hypoxia is a key feature of the tumour microenvironment\, a
 nd presents a major clinical and therapeutic challenge as it enables tumou
 rs to survive\, metastasize and resist killing by front-line treatments. M
 y 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 enable
 d us to identify and develop novel small molecule HIF signalling inhibitor
 s.  \n\nHypoxia and HIF activation\, as well as oncogenic and proliferativ
 e signals are known to drive metabolic adaptive responses primarily throug
 h transcriptional (and epigenetic) re-programming that in part promote a s
 hift 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 multip
 le means\, including basal oxygen consumption rate (OCR)\, metabolic inter
 mediates 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 tumor
 igenesis through control of tumour metabolic adaptive responses and tumour
  cell survival/growth are not understood.\n\nThus\, we have been investiga
 ting the cross-talk between mitochondria and hypoxia (and HIF) signalling.
  Previously\, we discovered the redox-sensitive mitochondrial import prote
 in\, coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCH
 D4) is critical for controlling intracellular oxygenation\, hypoxia signal
 ling 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 gen
 e in cancer irrespective of aetiology. CHCHD4 provides an import and oxido
 reductase-mediated protein folding function along with the sulfhydryl oxid
 ase GFER (ALR/Erv1) as a key component of the mitochondrial disulfide rela
 y system (DRS) within the intermembrane space (IMS). In this way\, CHCHD4 
 participates in electron transfer to complex IV (CIV)\, the molecular oxyg
 en acceptor of the respiratory chain. Overexpression of CHCHD4 in a range 
 of human cancers correlates with increased tumour progression\, disease re
 currence and poor patient survival\, and provides a proliferative and meta
 bolic advantage to tumour cells in both normoxia and hypoxia.  Using our n
 ovel small molecule HIF inhibitors\, genome-wide CRISPR/Cas9 deletion scre
 ening\, global proteomic and SILAC analyses\, as well as a range of unique
  cell and model systems that we have generated\, we have been investigatin
 g how the CHCHD4-HIF axis works\, and how the CHCHD4-HIF axis contributes 
 to tumorigenesis. 
LOCATION:Sackler Lecture Theatre (Level 7) The Keith Peters Building\, Cam
 bridge Biomedical Campus
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