RCUK Academic Fellow and University Lecturer
Tel: +44 (0)1223 333863, Fax: 0870 1357474, E-mail: email@example.com
Mitochondrial Physiology in Health and Disease
For all processes of life to occur, an input of energy is required. Organisms therefore depend critically on the metabolic pathways used to convert fuel energy into useful forms. Central to this process in almost all mammalian cells are the mitochondria, often termed the molecular powerhouses.
In the mitochondria, metabolic fuels, such as glucose, fatty acids and ketone bodies, are oxidized to produce the reduced intermediates NADH and FADH2, which pass electrons to complexes I and II, respectively, of the electron transport chain. Electrons pass through complexes I-IV of the chain to the final acceptor, O2, in a series of redox reactions with the free energy released being used to drive the synthesis of ATP from ADP and inorganic phosphate (Pi), and thus fuel and oxygen consumption is coupled to ADP phosphorylation. This concept underlies the chemiosmotic principle described by Peter Mitchell, for which he was awarded the Nobel Prize in Chemistry in 1978.
Mitochondria therefore require a supply of substrates and oxygen in order to produce ATP and thus support normal cellular function. Mitochondria are also a major source of reactive oxygen species (ROS) – metabolic by-products that play a role in cell signaling but at high concentrations can damage proteins, lipids and DNA (including mitochondrial DNA), leading to decline of function. Mitochondrial ROS production is increased when oxygen supply does not match demand; thus, the major consequences of mitochondrial dysfunction are energy (ATP) depletion and cellular damage.
Our work is concerned with mitochondrial function; how this is altered in metabolic diseases, during development and ageing, and with changes in diet, exercise and oxygen; and what effects these changes have on physiological performance. We aim to elucidate the causes of mitochondrial dysfunction and the impact this has on function at the level of the tissue, intact organ and whole body.
We collaborate widely, and in particular members of the group are active members of the Centre for Trophoblast Research here at the University of Cambridge, and the Centre for Altitude, Space and Extreme Environment Medicine at UCL, where Andrew Murray is a member of the Scientific Strategy Committee of the Caudwell Xtreme Everest Research Group.
Mr Tom Ashmore – PhD Student
Dr Helen Atherton – Postdoctoral Researcher
Dr Francesca Colleoni – Postdoctoral Researcher
Miss Floriane Faure – Visiting Student from January 2012
Mr James Horscroft – PhD Student
Miss Yun Huang – Part II Project Student
Miss Aleksandra Kotwica – PhD Student
Dr Andrea Morash – Postdoctoral Researcher
Prof Graham Burton (PDN)
Prof Kieran Clarke (University of Oxford)
Dr Julian Griffin (University of Cambridge)
Dr Mike Grocott (UCL)
Prof Hugh Montgomery (UCL)
Dr Martha Tissot van Patot (University of Colorado)
Our work has been supported by grants from Action Medical Research, BBSRC, BHF, Karim Rida Said Foundation, the Isaac Newton Trust and the Natural Science and Engineering Research Council of Canada.
AJ Murray, NS Knight, SE Little, LE Cochlin, M Clements, K Clarke. Dietary long-chain, but not medium-chain, triglycerides impair exercise performance and uncouple cardiac mitochondria in rats. Nutr Metab. In Press.
LD Roberts, AJ Murray, DA Menassa, T Ashmore, AW Nicholls, JL Griffin. The Contrasting roles of PPAR-δ and PPAR-γ Activation in White Adipose Tissue: the Metabolic Switch between Storing and Burning Fat. Genome Biol. In Press.
LM Edwards, CJ Holloway, AJ Murray, NS Knight, EE Carter, GJ Kemp, CH Thompson, DJ Tyler, S Neubauer, PA Robbins, K Clarke. Endurance exercise training blunts the deleterious effect of high-fat feeding on whole-body efficiency. Am J Physiol Regul Integr Comp Physiol. In Press.
CJ Holloway, LE Cochlin, Y Emmanuel, A Murray, I Codreanu, LM Edwards, C Szmigielski, DJ Tyler, NS Knight, BK Saxby, B Lambert, C Thompson, S Neubauer, K Clarke. A high fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in normal human subjects. Am J Clin Nutr. 93: 748-55, 2011.
MA Cole, AJ Murray, LE Cochlin, LC Heather, S McAleese, NS Knight, A Abd Jamil, E Sutton, N Parassol, K Clarke. A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. Basic Res Cardiol. 106: 447-57, 2011.
LM Edwards, AJ Murray, CJ Holloway, EE Carter, GJ Kemp, I Codreanu, H Brooker, DJ Tyler, PA Robbins, K Clarke. Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men. FASEB J. 25: 1088-96, 2011.
CJ Holloway, HE Montgomery, AJ Murray, LE Cochlin, I Codreanu, N Hopwood, AW Johnson, OJ Rider, DZH Levett, DJ Tyler, JM Francis, S Neubauer, MPW Grocott, K Clarke. The Cardiac Response to Hypobaric Hypoxia: Persistent changes in cardiac mass, function and energy metabolism after a trek to Mt Everest Base Camp. FASEB J. 25: 792-6, 2011.
Y Kashiwaya, R Pawlosky, W Markis, MT King, C Bergman, S Srivastava, A Murray, K Clarke, RL Veech. A ketone ester diet increased brain malonyl CoA and uncoupling protein 4 and 5 while decreasing food intake in the normal Wistar rat. J Biol Chem. 285: 25950-6, 2010.
LM Edwards, AJ Murray, DJ Tyler, GJ Kemp, CJ Holloway, PA Robbins, S Neubauer, D Levett, HE Montgomery, MP Grocott, K Clarke; Caudwell Xtreme Everest Research Group. The effect of high-altitude on human skeletal muscle energetics: P-MRS results from the Caudwell Xtreme Everest expedition. PLoS One. 5: e10681, 2010.
MC Tissot van Patot, AJ Murray, V Becky, T Cindrova-Davies, J Johns, E Jauniaux, GJ Burton, NJ Serkova. Human placental metabolic adaptation to chronic hypoxia, high altitude: Hypoxic pre-conditioning. Am J Physiol Regul Integr Comp Physiol. 298: R166-72, 2010.
AJ Murray. Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could solve the controversies. Genome Med. 1: 117, 2009.
AJ Murray, NS Knight, LE Cochlin, S McAleese, RM Deacon, JN Rawlins, K Clarke. Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding. FASEB J. 23: 4353-60, 2009.
AJ Murray, MA Cole, CA Lygate, CA Carr, DJ Stuckey, SE Little, S Neubauer, K Clarke. Increased mitochondrial uncoupling proteins, respiratory uncoupling and decreased efficiency in the chronically infarcted rat heart. J Mol Cell Cardiol. 44: 694-700, 2008.
OJ How, TS Larsen, AD Hafstad, A Khalid, ES Myhre, AJ Murray, NT Boardman, M Cole, K Clarke, DL Severson, E Aasum. Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice. Arch Physiol Biochem. 113: 211-20, 2007.
AJ Murray, LM Edwards, K Clarke. Mitochondria in Heart Failure. Curr Opin Clin Nutr Metab Care. 10: 704-711, 2007.
LC Heather, MA Cole, CA Lygate, DJ Stuckey, AJ Murray, S Neubauer, K Clarke. Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovascular Res. 72: 430-7, 2006.
AJ Murray, CA Lygate, MA Cole, S Neubauer, K Clarke. Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart. Cardiovascular Res. 71: 149-57, 2006.
AJ Murray, M Panagia, D Hauton, GF Gibbons, K Clarke. Plasma free fatty acids and peroxisome proliferator-activated receptor α in the control of myocardial uncoupling proteins. Diabetes. 54: 3496-502, 2005.
AJ Murray, RE Anderson, GC Watson, GK Radda, K Clarke. Uncoupling proteins in human heart. Lancet. 364: 1786-1788, 2004.
ME Bollard, AJ Murray, K Clarke, JK Nicholson, JL Griffin. A study of metabolic compartmentation in the rat heart and cardiac mitochondria using high resolution magic angle spinning 1H NMR spectroscopy. FEBS Lett. 553: 73-8, 2003.