Mike Murphy

mpm [at] mrc-mbu [dot] cam [dot] ac [dot] uk

Tel.: +44 (0)1223 252900

Mitochondrial dysfunction

Research area: Targeting 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.

Uptake of mitochondria-targeted antioxidants

Oral delivery and uptake of a mitochondria-targeted antioxidant into mitochondria in tissues.

Background information

We are trying to find out more about the roles of reactive oxygen species in mitochondria by developing probes to reactive oxygen that are targeted to the organelle.

We have developed a nitric oxide donor that is targeted to mitochondria for studying how nitric oxide modulates mitochondrial metabolism.

We are developing ways to measure thiol redox changes in mitochondria in response to oxidative stress and cell signalling.

Selected publications

Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijevic, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. M. J., Smith, A. C., Eyassu, F., Shirley, R., Hu,C. H.,Dare, A. J., James, A. M., Rogatti, S., Hartley, R. C., Eaton, S., Costa, A. S. H., Brookes, P. S., Davidson, S. M., Duchen, M. R., Saeb-Parsy, K., Shattock, M. J., Robinson, A J., Work, L. M., Frezza, C., Krieg, T. & Murphy, M. P. (2014).
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
Nature, 515, 431-435.

Schwarzländer, M., Wagner, S., Ermakova, Y. G., Belousov, V. V., Radi, R., Beckman, J. S., Buettner, G. R., Demaurex, N., Duchen, M. R., Forman, H. J., Fricker, M. D., Gems, D., Halestrap, A. P., Halliwell, B., Jakob, U., Johnston, I. G., Jones, N. S., Logan, D. C., Morgan, B., Müller, F. L., Nicholls, D. G., Remington, S. J., Schumacker, P. T., Winterbourn, C. C., Sweetlove, L. J., Meyer, A. J., Dick, T. P. & Murphy, M. P. (2014).
The ‘Mitoflash’ probe cpYFP does not respond to superoxide.
Nature, 514, E12-E14.

Pun, P. B. L., Logan, A., Darley-Usmar, V., Chacko, B., Johnson, M. S., Huang, G. W., Rogatti, S., Prime, T. A., Methner, C., Krieg, T., Fearnley, I. M., Larsen, L., Larsen, D. S., Menger, K. E., Collins, Y., James, A. M., Kumar, G. D. K., Hartley, R. C., Smith, R. A. J. & Murphy, M. P. (2014).
A mitochondria-targeted mass spectrometry probe to detect glyoxals: implications for diabetes.
Free Radic. Biol. Med. 67, 437-450.

Murphy, M. P. (2014).
Antioxidants as therapies: can we improve on nature?
Free Rad. Biol. & Med. 66, 20-23.

Chouchani, E. T., Methner, C., Nadtochiy, S. M., Logan, A., James, A. M., Cochemé, H. M., Partridge, L., Fearnley, I. M., Robinson, A. J., Hartley, R. C., Smith, R. A. J., Krieg, T., Brookes, P. S. & Murphy, M. P. (2013).
Cardio protection by S-nitrosation of a cysteine switch on mitochondrial complex I.
Nat. Med. 19, 753-762.

Cocheme, H. M., Logan, A. Prime., T. A., Abakumova, I., Quin, C., McQuaker, S. J., Patel, J. V., Fearnley, I. M., James, A. M., Smith, R. A. J., Hartley, R. C., Partridge, L. & Murphy. M. P. (2012).
Using the mitochondrial-targeted ratiometric mass spectronmetry probe MItoB to measure H202 with living Drosphilia.
Nat. Protoc. 7, 946-958.

Cochemé, H. M., Quin, C., Stephen J. McQuaker, S. J., Cabreiro, F., Logan, A., Prime, T. A., Abakumova, I., Patel, J. V., Fearnley, I. M., James, A. M., Porteous, C. M., Smith, R. A. J., Saeed, S., Carré, J. E., Singer, M., Gems, D., Hartley, R. C., Partridge, L. & Murphy, M. P. (2011).
Measurement of H2O2 within living drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix.
Cell Metab. 13, 340-350.

Murphy, M. P., Holmgren, A., Larsson, N-G., Halliwell, B., Chang, C. J, Kalyanaraman, B., Rhee, S. G., Paul J. Thornalley, P. J., Partridge, L. & Winterbourn, C. C. (2011).
Unraveling the biological roles of reactive oxygen species.
Cell Metab. 13, 361-366.