Projects per year
The mechanism of the mitochondrial permeability transition and its role in heart reperfusion injury:
In conditions such as ischaemic heart disease and stroke, mitochondria experience oxidative stress and become overloaded with Ca2+. This leads to the opening of a non-specific pore in the inner mitochondrial membrane, the mitochondrial permeability transition pore (MPTP), that destroys the functional integrity of mitochondria and leads to cell death. It can be inhibited by the immunosuppressant drugs Cyclosporin A and Sanglifehrin A.
We are studying the molecular mechanism of the MPTP and how its inhibition can protect the hearts from the damaging effects of ischaemia and reperfusion. One potent protective mechanism involves exposing hearts to brief ischaemic episodes prior to prolonged ischemia and we are investigating how this effect is mediated with a particular emphasis on the role of reactive oxygen species.
Lactic acid transport across the plasma membrane is essential in both glycolytic cells such as muscle and tumour, and also in the heart and liver, which utilise lactic acid. Fourteen distinct proton-linked monocarboxylate transporters (MCTs) have been described, each with a characteristic tissue distribution and role. An ancillary glycoprotein, basigin or embigin, is required for expression of MCT1 and MCT4 at the cell surface. Structure/function studies of MCTs and basigin are being undertaken by site-directed mutagenesis and molecular modeling, with the goal of developing isoform-specific inhibitors that may be effective chemotherapeutic agents for the treatment of cancer.
We are also seeking to identify the mammalian mitochondrial pyruvate carrier, that plays a central role in carbohydrate and fat metabolism.
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- 6 Finished
1/09/09 → 1/09/12
19/07/04 → 19/12/07
15/09/99 → 15/02/02
Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressorsScott, L. M., Vincent, E. E., Hudson, N., Neal, C. R., Jones, N., Lavelle, E. C., Campbell, M., Halestrap, A. P., Dick, A. D. & Theodoropoulou, S., 22 Apr 2021, In: JCI Insight. 6, 8, 21 p., e129429.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile3 Citations (Scopus)29 Downloads (Pure)
Maintenance of complex I and its supercomplexes by NDUF-11 is essential for mitochondrial structure, function and healthKnapp-Wilson, A. L., C. Pereira, G., Buzzard, E. J., Ford, H. C., Neal, C. R., Verkade, P., Halestrap, A. P., Gold, V. A. M., Kuwabara, P. E. & Collinson, I. R., 9 Jul 2021, In: Journal of Cell Science. 134, 13, 17 p., jcs258399.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile67 Downloads (Pure)
Hexokinase II dissociation alone cannot account for changes in heart mitochondrial function, morphology and sensitivity to permeability transition pore opening following ischemiaC. Pereira, G., Lee, L. J., Rawlings, N., Ouwendijk, J., Parker, J. E., Andrienko, T. N., Henley, J. M. & Halestrap, A. P., 24 Jun 2020, In: PLoS ONE. 15, 6, 29 p., e0234653.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile60 Downloads (Pure)