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Mitochondrial Efficiency
Mitochondria are central to energy metabolism in our cells and play critical roles in health and disease. The Crichton lab studies the molecular and bioenergetic processes that occur in mitochondria and how they may be influenced to improve health. Mitochondrial efficiency and the role of key membrane proteins, uncoupling proteins (UCP1-5) in particular, are a current research focus.
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Associate Professor Dr Paul Crichton
View my research profileI am a Group Leader at Norwich Medical School and currently co-direct the Biomedical Research Centre at UEA. Following my Biochemistry DPhil (University of Sussex), I carried out an MRC Career Development Fellowship and Investigator Scientist studies at the MRC Mitochondrial Biology Unit, Cambridge, before moving to UEA to set up my group with subsequent support from a BBSRC New Investigator Award.
We are often advertising research studentship and post doc positions (please see FindAPhD and jobs.ac.uk). Do get in touch if you would like to discuss these or any other research opportunities in our lab.
THE ACTIVATION OF UCP1 IN BROWN ADIPOSE TISSUE
Mitochondrial Uncoupling Protein 1 (UCP1) allows specialised brown adipose tissue of mammals to burn off calories as heat in response to cold temperatures. Thermogenesis of this nature increases glucose and triglyceride turnover and, if activated in humans, has potential to help combat obesity and diabetes. Active brown adipose tissue associates with improved glucose homeostasis and cardiometabolic health. Our studies have clarified important details in the composition, structure and mechanisms of activation and regulation of UCP1, and have identified novel ligand regulators and drug-like activators. Our advances are helping to understand how this and related mitochondrial processes may be promoted towards interventions for metabolic disease.
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Mitochondrial UCPs
UCP2-5 are expressed in various tissues and are implicated in metabolic disorders, inflammation, ischemic shock, neuronal dysfunction, cancer and aging. UCP2, in particular, has pathophysiological roles in diabetes and cancer and represents a putative therapeutic target. Emerging evidence suggests the protein transports 4-carbon metabolites from mitochondria to facilitate glutamine utilisation, acting as a metabolic switch in cells. Like many drug targets, UCPs are membrane proteins, which are challeging to study. Our studies have established methods to produce these proteins intact and study their ligand binding and functional properties by novel approaches. The molecular details gained here help clarify metabolic functioning and how such proteins may be influenced to improve health.
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Selected Publications
Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis, Jones, S. A., Ruprecht, J. J., Crichton, P. G. & Kunji, E. R. S. 2024, Trends in Biochemical Sciences. 49, 6, p. 506-519 14 p.
Two-stage evolution of mammalian adipose tissue thermogenesis, Keipert, S., Gaudry, M. J., Kutschke, M., Keuper, M., Dela Rosa, M. A. S., Cheng, Y., Monroy Kuhn, J. M., Laterveer, R., Cotrim, C. A., Giere, P., Perocchi, F., Feederle, R., Crichton, P. G., Lutter, D. & Jastroch, M. 2024, Science. 384, 6700, p. 1111-1117 7 p.
Structural basis of purine nucleotide inhibition of human uncoupling protein 1, Jones, S. A., Gogoi, P., Ruprecht, J. J., King, M. S., Lee, Y., Zögg, T., Pardon, E., Chand, D., Steimle, S., Copeman, D. M., Cotrim, C. A., Steyaert, J., Crichton, P. G., Moiseenkova-Bell, V. & Kunji, E. R. S. 2023, Science Advances. 9, 22, eadh4251.
Activating ligands of Uncoupling protein 1 identified by rapid membrane protein thermostability shift analysis, Cavalieri, R., Hazebroek, M. K., Cotrim, C. A., Lee, Y., Kunji, E. R. S., Jastroch, M., Keipert, S. & Crichton, P. G. 2022, Molecular Metabolism. 62, 101526.
The molecular mechanism of transport by the mitochondrial ADP/ATP carrier (2019) Ruprecht, J. J., King, M. S., Zögg, T., Aleksandrova, A. A., Pardon, E., Crichton, P. G., Steyaert, J. & Kunji, E. R. S. 2019, Cell. 176, 3, p. 435-447.e15 13 p.