The metabolite interactions of mitochondrial Uncoupling Protein-1 in regulating brown fat energy expenditure

CRICHTON_U23DTP

Mitochondria in our cells harness energy through the breakdown of nutrients to produce ATP through oxidative phosphorylation.

However, in specialised brown adipose tissue, popularised as ‘good fat’, the conventional process is ‘short circuited’ by a mitochondrial membrane protein, Uncoupling Protein 1 (UCP1), to allow the tissue to burn off calories as heat.

When engaged, the protein helps mammals fight cold temperatures and can contribute to calorie expenditure in humans to maintain metabolic health. Obesity and related conditions are a primary health concern in the UK and worldwide, estimated to affect up to a third of the UK population and ~2 billion people globally.

This is an exciting and timely opportunity to study the molecular processes of how UCP1 is activated.

The project will focus on determining novel ligand interactions of UCP1 with various metabolites that potentially act to regulate the protein, taking advantage of recent advances that we have made on the molecular nature of UCP1.

The student will be trained in an array of biochemical and molecular biology techniques to study isolated membrane protein (e.g. cloning, recombinant protein expression, membrane protein purification, liposome reconstitution assays, protein conformation analysis, novel ligand-binding assessment methodologies).

The project will also include methods to assess UCP1 activity in cultured mammalian cells (e.g. respirometric measurements, genetic manipulations) to consolidate key findings on UCP1 regulation and energy metabolism.

The student will gain a wealth of transferrable skills, invaluable for scientific career progression, and will be supervised by Dr Paul Crichton at the Biomedical Research Centre, where they will benefit from state-of-the-art facilities and research environment provided by Norwich Medical School, School of Biological Sciences and the surrounding Norwich Research Park.

They will gain valuable experience through exchange opportunities with the group’s national and international collaborators (e.g. the Jastroch group, Wenner Gren Institute/University of Stockholm).

References

Cavalieri R, Hazebroek MK, Cotrim CA, Lee Y, Kunji ERS, Jastroch M, Keipert S, Crichton PG. Activating ligands of Uncoupling protein 1 identified by rapid membrane protein thermostability shift analysis (2022) Mol Metab. 62:101526.

Ruprecht JJ, King MS, Zögg T, Aleksandrova AA, Pardon E, Crichton PG, Steyaert J, Kunji ERS. The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier (2019) Cell 176(3):435-447.e15 Crichton PG, Lee Y, Kunji. ER The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism (2017) Biochimie 134:35-50.

Lee Y, Willers C, Kunji ER, Crichton PG. Uncoupling protein 1 binds one nucleotide per monomer and is stabilized by tightly bound cardiolipin. (2015) Proc Natl Acad Sci U S A. 112:6973-8.