Mike Murphy

Programme Leader

Targeting therapeutic and probe molecules to mitochondria, mitochondrial radical production and redox signalling

Reactive oxygen species (ROS) produced by mitochondria cause oxidative damage that impairs the ability of mitochondria to make ATP and to carry out their metabolic functions. They may participate also in cellular redox signalling pathways. One important aspect of our work is to investigate how oxidative damage to mitochondria contributes to human pathologies. We have worked out a way of targeting small bioactive molecules, such as antioxidants, to mitochondria in order to counter the effects of ROS and to examine the effects of doing so at cellular and whole animal levels. The bioactive molecule is attached chemically to a lipophilic cation such triphenylphosphonium. These cations accumulate selectively, first in the cytosol, driven by the plasma membrane potential, and then several-hundred fold in the matrix of mitochondria, driven by the membrane potential across the inner membrane. A second important aspect is to determine whether and how mitochondrial ROS alters the activities of proteins in putative signalling and protective pathways by reversibly modifying the redox state of critical protein thiols in mitochondria. We use a range of free radical and proteomic approaches to identify the proteins involved, and to identify the cysteine residues and any redox modifications. Finally, we take this information and use it to rationally design potential therapies for diseases that arise from mitochondria dysfunction. Currently our main focus for therapy is the ischaemia/reperfusion injury that arises from stroke and heart attack.

Publication profile

Research areas

Mitochondrial Exomarkers

Mitochondrial Therapies

Thiol Proteomics

Group Members

Research support

Georgina Bates
Tracy Prime

Post-docs

Dr. Andrew James
Jan Miljkovic
Amin Mottahedin
Hiran Prag

Post-graduate students

Nils Burger
Alva Casey
Filip Cvetko
Anja Gruszczyk

Visitors

Margaret Huang
Dee (Duvaraka) Kulaveerasingam
Marie-Christine Laurent
John Mulvey
Johannes Reinhold

Publications

Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, Jedrychowski MP, Costa ASH, Higgins M, Hams E, Szpyt J, Runtsch MC, King MS, McGouran JF, Fischer R, Kessler BM, McGettrick AF, Hughes MM, Carroll RG, Booty LM, Knatko EV, Meakin PJ, Ashford MLJ, Modis LK, Brunori G, Sévin DC, Fallon PG, Caldwell ST, Kunji ERS, Chouchani ET, Frezza C, Dinkova-Kostova AT, Hartley RC, Murphy MP & O'Neill LA (2018) Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113-117
Shchepinova MM, Cairns AG, Prime TA, Logan A, James AM, Hall AR, Vidoni S, Arndt S, Caldwell ST, Prag HA, Pell VR, Krieg T, Mulvey JF, Yadav P, Cobley JN, Bright TP, Senn HM, Anderson RF, Murphy MP & Hartley RC (2017) MitoNeoD: A Mitochondria-Targeted Superoxide Probe. Cell Chem Biol
James AM, Hoogewijs K, Logan A, Hall AR, Ding S, Fearnley IM & Murphy MP (2017) Non-enzymatic N-acetylation of Lysine Residues by AcetylCoA Often Occurs via a Proximal S-acetylated Thiol Intermediate Sensitive to Glyoxalase II. Cell Rep 18, 2105-2112
Logan A, Pell VR, Shaffer KJ, Evans C, Stanley NJ, Robb EL, Prime TA, Chouchani ET, Cochemé HM, Fearnley IM, Vidoni S, James AM, Porteous CM, Partridge L, Krieg T, Smith RAJ & Murphy MP (2015) Assessing the Mitochondrial Membrane Potential in Cells and In Vivo using Targeted Click Chemistry and Mass Spectrometry. Cell Metab
Chouchani ET, Pell VR, Gaude E, Aksentijević D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord ENJ, Smith AC, Eyassu F, Shirley R, Hu C-H, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa ASH, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T & Murphy MP (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431-435
Chouchani ET, Methner C, Nadtochiy SM, Logan A, Pell VR, Ding S, James AM, Cochemé HM, Reinhold J, Lilley KS, Partridge L, Fearnley IM, Robinson AJ, Hartley RC, Smith RAJ, Krieg T, Brookes PS & Murphy MP (2013) Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med 19, 753-9

All publications

Biography

Education & Employment

1980-1984: BA in Chemistry, first class honours, first in class, Trinity College, Dublin, Ireland
1984-1987: PhD, Department of Biochemistry, University of Cambridge, UK
1988: Associate Research Scientist, Columbia University College of Physicians and Surgeons, New York
1989: Teacher with Voluntary Services Overseas (London) in Zimbabwe
1990-1992: Lecturer, Biochemistry Department, Trinity College, Dublin, Ireland
1992-2001: Lecturer/Senior Lecturer/Associate Professor, Biochemistry Department, University of Otago, New Zealand
1999: Sabbatical Visitor, Biozentrum, University of Basel, Switzerland
1999: Sabbatical Visitor, University of Alabama at Birmingham, USA
2000-2001: Associate Dean for Research, Otago School of Medical Sciences
2001-present: Programme Leader, MRC Mitochondrial Biology Unit, University of Cambridge, UK

Awards & honours

1982: C Walter Jones Prize in Organic Chemistry
1982-1987: Foundation Scholarship
1984: Cocker Medal for Experimental Chemistry
1984-1987: Open Research Studentship, Peterhouse, University of Cambridge
2000: Applied Biosystems Medal, NZ Society of Biochemistry and Molecular Biology
2000: Research Medal of the New Zealand Association of Scientists
2001-present: Honorary Fellow, Depts of Chemistry and Biochemistry, University of Otago
2008: The Nathan O. Kaplan Lecturer, University of California, San Diego
2012: Honorary Fellow of the Royal Society of New Zealand (Hon FRSNZ)
2016: Keilin Memorial Lecture and Medal
2016-present: Wellcome Trust Investigator
2016-present: Honorary Research Professor, Chemistry Department, University of Otago, NZ
2017: The 2017 Gopal Singhal Lecturer, Chemistry Department, Wayne State University, USA
2018: The 2018 Basic Science Lecturer, Society for Free Radical Research-Europe
2018-present: Personal Professorship, University of Cambridge

Editorial Boards

2016-present: Cell Metabolism: Editorial board
2012-present: Free Radical Biology and Medicine: Editorial board
2013-present: Redox Biology: Editorial board
2013-present: Redox Report: Editorial board
2010-present: Free Radical Research: Editorial board
2017-present: British Heart Foundation: Project grants committee
2017-present: Novintum Biotech, Switzerland: Scientific advisory board
2001-present: Antipodean Pharmaceuticals, New Zealand: Scientific advisory board
2017-present: EU H2020 FET-Open program (Future and Emerging Technologies) - Lumiblast: Expert monitor
Present: Takeda Pharmaceuticals, Japan; Cayman Chemicals, USA; Flagship Ventures, USA: Consultant
2003-2016: Biochemical Journal: Deputy chair (2007-2016), Editorial board (2003-2016)
1999-2014: Archives of Biochemistry and Biophysics: Editorial board
2009-2011: Current Opinion in Investigational New Drugs: Editorial board
2002-2015: FEBS Journal: Editorial advisory panel
2003–2007: Biochemical Society Theme Panel III (Bioenergetics and Metabolism)
2010-2013: Telethon Italy: Scientific committee
2009-2011: Buck Institute for Aging Research, USA: External advisory board for the U54 Interdisciplinary Research Center

Patents

Mitochondrially targeted antioxidants, Michael P. Murphy and Robin A. J. Smith, United States Patent US 6,331,532.

Mitochondrially targeted antioxidants, Michael P. Murphy and Robin A. J. Smith, United States Patent US 6,984,636.

Mitochondrially targeted antioxidants, Michael P. Murphy and Robin A. J. Smith, Australian Patent AU 763179.

Mitochondrially targeted antioxidants, Michael P. Murphy and Robin A. J. Smith, New Zealand Patent NZ 505352.

Mitochondrially targeted antioxidants, Michael P. Murphy and Robin A. J. Smith, United States Patent US 7,109,189.

Mitochondrially targeted antioxidants, Michael P. Murphy and Robin A. J. Smith, New Zealand Patent NZ 538371.

Triphenylphosphonium thionitrite nitric oxide donors, Michael P. Murphy and Robin A. J. Smith European Patent EP2066680.

Triphenylphosphonium thionitrite nitric oxide donors, Michael P. Murphy and Robin A. J. Smith. Canadian Patent CA 2664744.

Triphenylphosphonium thionitrite nitric oxide donors, Michael P. Murphy and Robin A. J. Smith. United States Patent US 12/732,909.

Mitoquinone derivatives used as mitochondrially targeted antioxidants, Michael P. Murphy and Robin A. J Smith, United States patent US 7,888,334.

Mitochondrially targeted antioxidants, Michael P Murphy and Robin A. J Smith, Canadian Patent CA 2311318

Websites

Lab Alumni with Faculty Positions:

Helena Cocheme - MRC Clinical Sciences Centre, London, UK

Jan Trnka - Charles University, Prague, Czech Republic

Christina Dahm - Aarhus University, Aarhus, Denmark

Aleksandra Filipovska - Harry Perkins Institute of Medical Research, Perth, Australia

Thomas Hurd - University of Toronto, Toronto, Canada

Edward Chouchani - Harvard Medical School and Dana-Farber Cancer Institute, Boston, USA

Collaborator Websites

Cambridge Biorepository for Translational Research

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