Professor of Hypoxia Signalling and Cell Biology
Research
Research Overview
The main goal of the Ashcroft laboratory is to understand the key cellular mechanisms involved in oxygen sensing and hypoxia signalling in mammalian cells. In particular, we have a strong interest in the hypoxia inducible factor (HIF) family of transcription factors and their role in cancer, renal disease and cardiovascular disease.
We are interested in how the oxygen sensing machinery controls cell function and adaptive processes that are associated with a variety of diseases including cancer, renal disease and cardiovascular disease. Our work primarily focuses on the heterodimeric transcription factor family, hypoxia inducible factor (HIF). HIF-1, the prototype of the family is composed of α and β subunits. Regulation of HIF-1 activity is primarily via the HIF-1α subunit, which is rapidly turned over via ubiquitin-mediated degradation by the proteosome; however, the HIF-1β subunit is constitutively expressed. In response to low oxygen tension (hypoxia), HIF-1α protein is stabilised and localises to the nucleus where it binds to HIF-1β and recruits transcriptional coactivators.
Research Aims
Our main goals are to:
1) Evaluate known and novel regulators of the hypoxia/HIF signalling with particular focus on link between mitochondria and the cellular oxygen-sensing machinery.
2) Investigate the key cellular mechanisms regulating hypoxia/HIF signalling in mammalian cells and elucidate how these are mechanistically linked to disease.
3) Identify and develop strategies to exploit hypoxia/HIF signalling in disease.
Publications
Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress. BMC Biol 2021 Dec
Genome-wide CRISPR/Cas9 deletion screen defines mitochondrial gene essentiality and novel routes for tumour cell viability in hypoxia. Thomas LW, Esposito E, Morgan RE, Price S, Young J, Williams SP, Maddalena LA, McDermott U, and Ashcroft M. Communications Biology. 2021 May 21;615:4. doi: 10.1038/s42003-021-02098-x.
CHCHD4 (MIA40) and the mitochondrial disulfide relay system. Al-Habib H, Ashcroft M.Biochem Soc Trans. 2021 Feb 26;49(1):17-27. doi: 10.1042/BST20190232.PMID: 33599699
Corrigendum: VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function Front Oncol 2021 Jan
CHCHD4 regulates tumour proliferation and EMT-related pheotypes, through respiratory chain-mediate metabolism. Thomas LW, Esposito C, Stephen JM, Costa ASH, Frezza C, Blacker TS, Szabadkai G, Ashcroft M. Cancer Metab. 2019 Jul 16;7:7. doi: 10.1186/s40170-019-0200-4.
Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria. Thomas LW, Ashcroft M. Cell Mol Life Sci. 2019 May;76(9):1759-1777. doi: 10.1007/s00018-019-03039-y.
CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain. Thomas LW, Stephen JM, Esposito C, Hoer S, Antrobus R, Ahmed A, Al-Habib H, Ashcroft M. Cancer Metab. 2019 Mar 6;7:2. doi: 10.1186/s40170-019-0194-y. eCollection 2019.
VHL-mediated regulation of CHCHD4 and mitochondrial function. Briston T., Stephen J., Thomas L.W., Esposito C., Chung Y.L., Syafruddin S., Turmaine M., Maddalena L., Greef B., Szabadkai G., Maxwell P.H., Vanharanta S. and Ashcroft M. Front Oncology (2018) 8: 388.
Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria. Thomas LW, Ashcroft M. Cell Mol Life Sci. 2019 Feb 14. doi: 10.1007/s00018-019-03039-y. [Epub ahead of print] Review.
VHL-mediated regulation of CHCHD4 and mitochondrial function. Briston T., Stephen J., Thomas L.W., Esposito C., Chung Y.L., Syafruddin S., Turmaine M., Maddalena L., Greef B., Szabadkai G., Maxwell P.H., Vanharanta S. and Ashcroft M. Front Oncology (2018) 8: 388.
The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo. Erdogan A.J., Ali M., Habich M., Salscheider S.L., Schu L., Petrungaro C., Thomas L.W., Ashcroft M., Leichert L.I., Roma L.P. and Riemer J. Redox Biol (2018) 17: 200-206.
CHCHD4 regulates intracellular oxygenation and perinuclear distribution of mitochondria. Thomas L.W., Staples O., Turmaine M., Ashcroft M. Frontiers in Oncology (2017) 7: 71.
Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression. Yang J., Staples O., Thomas L.W., Briston T., Robson M., Poon E., Simões M.L., El-Emir E., Buffa F.M., Ahmed A., Annear N.P., Shukla D., Pedley B.R., Maxwell P.H., Harris A.L., Ashcroft M. J Clin Invest (2012) 122: 600-611.
HIF-1alpha localization with mitochondria: A new role for an old favorite? Briston, T., Yang J., Ashcroft M. Cell Cycle (2011) 10: 4170-4171.
