Honorary Consultant Physician, Cambridge University Hospitals NHS Foundation Trust.
Tel: 01223 762584
The heart is a highly metabolic organ and as such is full of energy-producing mitochondria. During a heart attack, blockage of a coronary artery prevents blood flow to part of the heart, a condition termed ischaemia. As a result, the mitochondria in this tissue are deprived of oxygen and energy production stops. We have demonstrated that one of the mitochondrial fuels, succinate, is build up during ischaemia and decreases again rapidly as soon as the blood flow is restored. During this so-called reperfusion phase succinate is actually consumed by the mitochondria via an alternative route that does not produce energy but instead produces oxygen radicals that destroy the heart muscle. Because lost heart muscle cannot be regenerated the patient is left with a weakened heart and heart failure often occurs. Our research is directed toward identifying therapies that prevent cell death in ischaemic heart and the subsequent development of heart failure. In addition, we aim to develop treatment strategies targeting heart failure in disease models such as obesity, type 1 and type 2 diabetes, and ageing.
To study heart attack and heart failure we perform procedures that closely resemble these conditions in patients and we subsequently evaluate tissue damage, mitochondrial function and cardiac health.
- ERASMUS: Fabio Di Lisa, Dipartimento di Scienze Biomediche Sperimentali, Università degli Studi di Padova, Italy
- Michael Murphy, MRC Mitochondrial Biology Unit, Cambridge
- Christian Frezza, MRC Cancer Unit, Cambridge
- Wolfson Brain Imaging Centre Cambridge
- James Downey, Department of Physiology, University of South Alabama, USA
- University of Paris Est Creteil, France
- Zhelong Xu, Tianjin Medical University, Department of Physiology and Pathophysiology
- Logan A, Pell VR, Shaffer KJ, Evans C, Stanley NJ, Robb EL, Prime TA, Chouchani ET, Cocheme HM, Fearnley IM, Vidoni S, James AM, Porteous CM, Partridge L, Krieg T, Smith RAJ, Murphy MP. Assessing the Mitochondrial Membrane Potential in Cells and In Vivo using Targeted Click Chemistry and Mass Spectrometry. Cell Metab.
- Chouchani ET, Pell VR, James AM, Work LM, Saeb-Parsy K, Frezza C, Krieg T, Murphy MP. A Unifying Mechanism for Mitochondrial Superoxide Production During Ischemia-Reperfusion Injury. Cell Metabolism, 23(2). 254-263.
- Chouchani ET, Pell VR, Gaude E, Aksentijević D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord EN, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa AS, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014. doi: 10.1038/nature13909. Nature, 515(7527), 431–5
- Methner C, Chouchani ET, Buonincontri G, Pell VR, Sawiak SJ, Murphy MP, Krieg T. Mitochondria selective S-nitrosation by mitochondria-targeted S-nitrosothiol protects against post-infarct heart failure in mouse hearts. Eur J Heart Fail. 2014;16(7):712-7. doi: 10.1002/ejhf.100. 2014
- Guido Buonincontri, Carmen Methner, Thomas Krieg, T. Adrian Carpenter, Stephen J. Sawiak. Trajectory correction for free-breathing radial cine MRI. Magn Reson Imaging. 2014. doi: 10.1016/j.mri.2014.04.006. 2014
- Guido Buonincontri, Carmen Methner, Thomas Krieg, T. Adrian Carpenter and Stephen J. Sawiak Functional assessment of the mouse heart by MRI with a 1-min acquisition. NMR Biomed. 2014. doi: 10.1002/nbm.3116. 2014
- Edward T. Chouchani, Chou-Hui Hu, Guido Buonincontri, Carmen Methner, Angela Logan, Chou-Hui Hu, Stephen J. Sawiak, Michael P. Murphy, and Thomas Krieg. Complex I deficiency due to selective loss of Ndufs4 in the mouse heart results in severe hypertrophic cardiomyopathy. PLoS One, 10.1371/journal.pone.0094157. 2014
- Carmen Methner, Guido Buonincontri, Chou-Hui Hu, Ana Vujic, Axel Kretschmer, Stephen Sawiak, Adrian Carpenter, Johannes-Peter Stasch, Thomas Krieg. Riociguat reduces infarct size and post-infarct heart failure in mouse hearts: insights from MRI/PET imaging. PLoS One, 10.1371/journal.pone.0083910. 2013
- Guido Buonincontri, Carmen Methner, T. Adrian Carpenter, Robert C. Hawkes, Stephen J. Sawiak, Thomas Krieg. MRI and PET in mouse models of myocardial infarction. J Vis Exp. doi: 10.3791/50806. 2013
- Edward T. Chouchani, Carmen Methner, Sergiy M. Nadtochiy, Angela Logan, Victoria R. Pell, Shujing Ding, Andrew M. James, Helena M. Cochemé, Johannes Reinhold, Kathryn S. Lilley, Linda Partridge, Ian M. Fearnley, Alan J. Robinson, Richard C. Hartley, Robin A.J. Smith, Thomas Krieg, Paul S. Brookes, and Michael P. Murphy. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nature Medicine. 19, 753-759. 2013 (Download) (Nature Medicine: News and Views) (BBC News coverage)
- Angela Logan, Helena M. Cochemé, Pamela Boon Li Pun, Nadezda Apostolova, Robin A. J. Smith, Lesley Larsen, David S. Larsen, Andrew M. James, Ian M. Fearnley, Sebastian Rogatti, Tracy A. Prime, Peter Finichiu, Anna Dare, Edward T. Chouchani, Victoria R. Pell, Carmen Methner, Caroline Quin, Stephen J. McQuaker, Thomas Krieg, Richard C. Hartley, Michael P. Murphy. Using exomarkers to assess mitochondrial reactive species in vivo. Biochimica Biophysica Acta. 2013 (online ahead of print) (Download)
- Carmen Methner, Robert Lukowski, Karina Grube, Florian Loga, Robin A. J. Smith, Michael P. Murphy, Franz Hofmann, Thomas Krieg. Protection through postconditioning or a mitochondria-targeted S-nitrosothiol is unaffected by cardiomyocyte-selective ablation of protein kinase G. Basic Research in Cardiology. 108, 337. (Download) 2013
- Guido Buonincontri, Carmen Methner, Thomas Krieg, T. Adrian Carpenter, Stephen J. Sawiak. A fast protocol for infarct quantification in mice. Journal of Magnetic Resonance Imaging. (DOI: 10.1002/jmri.24001) 2013