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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 James Horscroft – PhD Student
Miss Aleksandra Kotwica – PhD Student
Previous Team Members
Dr Tom Ashmore
Dr Helen Atherton
Dr Francesca Colleoni
Mr David Menassa
Dr Andrea Morash
Dr Augustine Ocloo
Professor Graham Burton (PDN)
Professor Kieran Clarke (University of Oxford)
Professor Martin Feelisch (University of Southampton)
Professor Abby Fowden (PDN)
Professor Erich Gnaiger (University of Innsbruck)
Dr Julian Griffin (University of Cambridge)
Professor Mike Grocott (University of Southampton)
Professor Hugh Montgomery (UCL)
Dr Amanda Sferruzzi-Perri (PDN)
Our work has been supported by grants from Action Medical Research, BBSRC, BHF, the Physiological Society, the Alborada Research Fund, Karim Rida Said Foundation, the Isaac Newton Trust and the Natural Science and Engineering Research Council of Canada.
Publications (see my Google Scholar profile for up-to-date citation counts)
Holloway CJ, Murray AJ, Mitchell K, Martin DS, Johnson AW, Cochlin LE, Codreanu I, Dhillon S, Rodway GW, Ashmore T, Levett DZH, Neubauer S, Montgomery HE, Grocott MPW, Clarke K (2014) Oral coenzyme Q10 supplementation does not prevent cardiac alterations during a high altitude trek to Everest Base Camp. High Altitude Medicine and Biology, In Press.
Yung HW, Colleoni F, Atkinson D, Cook E, Murray AJ, Burton GJ, Charnock-Jones DS (2014) Influence of speed of sample processing on placental energetics and signalling pathways: Implications for tissue collection. Placenta 35, 103-108.
Astin R, Bentham R, Djafarzadeh S, Horscroft JA, Kuc RE, Leung PS, Skipworth JRA, Vicencio JM, Davenport AP, Murray AJ, Takala J, Jakob SM, Montgomery H, Szabadkai G (2013) No evidence for a local renin-angiotensin system in liver mitochondria. Sci Rep 3, 2467.
Morash AJ, Kotwica AO, Murray AJ (2013) Tissue-specific changes in fatty acid oxidation in hypoxic heart and skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 305, R534-R541
Colleoni F, Padmanabhan N, Yung H-W, Watson ED, Cetin I, Tissot van Patot MC, Burton GJ, Murray AJ (2013) Suppression of mitochondrial electron transport chain function in the hypoxic human placenta: a role for miRNA210 and protein synthesis inhibition. PLoS One 8, e55194.
Murray AJ (2013) Of mice and men (and muscle mitochondria). Experimental Physiology 98, 879-880.
Wilson MH, Davagnanam I, Holland G, Dattani RS, Tamm A, Hirani SP, Kolfschoten N, Strycharczuk L, Green C, Thornton JS, Wright A, Bradwell AR, Edsell M, Kitchen ND, Murray A, Holloway CJ, Clarke K, Grocott M, Montgomery H, Imray C (2013) The cerebral venous system and anatomical predisposition to high altitude headache. Annals of Neurology 73, 381-389.
Chimerel C, Murray AJ, Oldewurtel ER, Summers DK, Keyser UF (2013) The effect of bacterial signal indole on the electrical properties of lipid membranes. Chemphyschem 14, 417-423.
Murray AJ (2012) Oxygen delivery and fetal-placental growth: Beyond a question of supply and demand? Placenta 33(Suppl. 2), e16-e22.
Agathocleous M, Love NK, Randlett O, Harris JJ, Liu J, Murray AJ, Harris WA (2012) Metabolic differentiation in the embryonic retina. Nat Cell Biol 14, 859-864.
Clarke K, Tchabanenko K, Pawlosky R, Carter E, Knight NS, Murray AJ, Cochlin LE, King MT, Wong AW, Roberts A, Robertson J, Veech RL (2012) Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Regul Toxicol Pharm 63, 196-208.
Charalambous M, Ferron SR, da Rocha ST, Murray AJ, Rowland T, Ito M, Schuster-Gossler K, Hernandez A, Ferguson-Smith AC (2012) Imprinted Gene Dosage Is Critical for the Transition to Independent Life. Cell Metabolism 15, 209-221.
Levett DZ, Radford EJ, Menassa DA, Graber EF, Morash AJ, Hoppeler H, Clarke K, Martin DS, Ferguson-Smith AC, Montgomery HE, Grocott MP, Murray AJ (2012) Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J 26, 1431-1441.
Colleoni F, Morash AJ, Ashmore T, Monk M, Burton GJ, Murray AJ (2012) Cryopreservation of placental biopsies for mitochondrial respiratory analysis. Placenta 33, 122-123.
Murray AJ (2011) Taking a HIT for the heart: why training intensity matters. J Appl Physiol 111, 1229-1230.
Roberts LD, Murray AJ, Menassa D, Ashmore T, Nicholls AW, Griffin JL (2011) The contrasting roles of PPARδ and PPARγ in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue. Genome Biol 12, R75.
Murray AJ, Knight NS, Little SE, Cochlin LE, Clements M, Clarke K (2011) Dietary long-chain, but not medium-chain, triglycerides impair exercise performance and uncouple cardiac mitochondria in rats. Nutr Metab (Lond) 8, 55.
Edwards LM, Holloway CJ, Murray AJ, Knight NS, Carter EE, Kemp GJ, Thompson CH, Tyler DJ, Neubauer S, Robbins PA, Clarke K (2011) Endurance exercise training blunts the deleterious effect of high-fat feeding on whole body efficiency. Am J Physiol Regul Integr Comp Physiol 301, R320-R326.
Holloway CJ, Cochlin LE, Emmanuel Y, Murray A, Codreanu I, Edwards LM, Szmigielski C, Tyler DJ, Knight NS, Saxby BK, Lambert B, Thompson C, Neubauer S, Clarke K (2011) A high fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in normal human subjects. Am J Clin Nutr 93, 748-755.
Cole MA, Murray AJ, Cochlin LE, Heather LC, McAleese S, Knight NS, Abd Jamil A, Sutton E, Parassol N, Clarke K. A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart (2011) Basic Res Cardiol 106, 447-457.
Edwards LM, Murray AJ, Holloway CJ, Carter EE, Kemp GJ, Codreanu I, Brooker H, Tyler DJ, Robbins PA, Clarke K (2011) Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men. FASEB J 25, 1088-1096.
Holloway CJ, Montgomery HE, Murray AJ, Cochlin LE, Codreanu I, Hopwood N, Johnson AW, Rider OJ, Levett DZ, Tyler DJ, Francis JM, Neubauer S, Grocott MP, Clarke K (2011) 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, 792-796.
Kashiwaya Y, Pawlosky R, Markis W, King MT, Bergman C, Srivastava S, Murray A, Clarke K, Veech RL (2010) 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, 25950-25956.
Edwards LM, Murray AJ, Tyler DJ, Kemp GJ, Holloway CJ, Robbins PA, Neubauer S, Levett D, Montgomery HE, Grocott MP, Clarke K (2010) The effect of high-altitude on human skeletal muscle energetics: P-MRS results from the Caudwell Xtreme Everest expedition. PLoS One 5, e10681.
Murray AJ (2009) Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could solve the controversies. Genome Medicine 1, 117.
Tissot van Patot MC, Murray AJ, Becky V, Cindrova-Davies T, Johns J, Jauniaux E, Burton GJ, Serkova NJ (2010) Human placental metabolic adaptation to chronic hypoxia, high altitude: Hypoxic pre-conditioning. Am J Physiol Regul Integr Comp Physiol 298, R166-R172.
Murray AJ, Knight NS, Cochlin LE, McAleese S, Deacon RM, Rawlins JN and Clarke K (2009) Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding. FASEB J 23, 4353-4360.
Murray AJ, Cole MA, Lygate CA, Carr CA, Stuckey DJ, Little SE, Neubauer S, Clarke K (2008) Increased mitochondrial uncoupling proteins, respiratory uncoupling and decreased efficiency in the chronically infarcted rat heart. J Mol Cell Cardiol 44, 694-700.
How OJ, Larsen TS, Hafstad AD, Khalid A, Myhre ES, Murray AJ, Boardman NT, Cole M, Clarke K, Severson DL, Aasum E (2007) Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice. Arch Physiol Biochem 113, 211-220.
Murray AJ, Edwards LM, Clarke K (2007) Mitochondria in heart failure. Curr Opin Clin Nutr Metab Care 10, 704-711.
Heather LC, Cole MA, Lygate CA, Stuckey DJ, Murray AJ, Neubauer S, Clarke K (2006) Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovascular Res 72, 430-437.
Murray AJ, Lygate CA, Cole MA, Neubauer S, Clarke K (2006) Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart. Cardiovascular Res 71, 149-157.
Murray AJ, Panagia M, Hauton D, Gibbons GF, Clarke K (2005) Plasma free fatty acids and peroxisome proliferator-activated receptor α in the control of myocardial uncoupling proteins. Diabetes54, 3496-3502.
Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K (2004) Uncoupling proteins in human heart. Lancet 364, 1786-1788.
Bollard ME, Murray AJ, Clarke K, Nicholson JK, Griffin JL (2003) A study of metabolic compartmentation in the rat heart and cardiac mitochondria using high resolution magic angle spinning 1H NMR spectroscopy. FEBS Lett 553, 73-78.
Above: The pathways of energy metabolism converge on the mitochondrion.
Above: Respiration trace of mitochondria isolated from rat heart.
Above: James and Aleks carry out high-resolution respirometry to measure mitochondrial function in human muscle samples at the Xtreme Everest 2 laboratory, Mt Everest Base Camp, Nepal, 2013.