Research groups

Andrew Halestrap
Professor

+44 (0)117 33 12118 (tel)
+44 (0)117 33 12168 (fax)
a.halestrap@bristol.ac.uk

Research

Mitochondria and cell death; membrane transporters.

• 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 mitochon-drial 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 investigating 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.

• Monocarboxylate transport:  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 mono-carboxylate transporters (MCTs) have been described, each with a characteristic tissue distribution and role.  

  An ancillary glycoprotein, basigin, 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 modelling, and mechanisms involved in the regulation of different MCT isoforms investigated. We have recently cloned the yeast mitochondrial pyruvate carrier, that plays a central role in carbohydrate and fat metabolism, and are currently endeavouring to do the same for the mammalian carrier.

Group

Maz Wilson, Philippe Pasdois, Igor Khaliulin, Andrew Green, Matthew Ovens, Pinadda Varanyuwatana, Jo Parker, and Agnieszka Bierzynska.

Recent publications

Leung AW, Halestrap, A.P. (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta. 1777(7-8): 946-52.

Clarke SJ, Khaliulin I, Das M, Parker JE, Heesom KJ, Halestrap, A.P. (2008)Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation. Circ Res. 102(9): 1082-90.

Halestrap, A.P. Clarke SJ, Khaliulin I. (2007) The role of mitochondria in protection of the heart by preconditioning. Biochim Biophys Acta. 1767(8): 1007-31. Review.

Khaliulin I, Clarke SJ, Lin H, Parker J, Suleiman MS, Halestrap, A.P. (2007) Temperature preconditioning of isolated rat hearts--a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore. J Physiol. 581(Pt 3): 1147-61.