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Targeting molecules to mitochondria, mitochondrial radical production, thiol redox state and redox signalling

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Targeting molecules to mitochondria

Bioactive molecules can be targeted to mitochondria within cells by linking them to lipophilic cations. These molecules include antioxidants, thiol probes and sensors of changes in mitochondrial radical production. Currently we are using these novel probes to investigate mitochondrial radical production, thiol changes, interaction with nitric oxide and mitochondrial turnover in a range of biological systems. In addition to these ongoing studies in biochemistry and cell biology, we are also developing new mitochondrially targeted molecules, including enzyme mimetics. There is considerable scope for a candidate with a strong background in chemistry who has an interest in working at the interface of Chemistry and Biology to help develop new compounds.




Funding Notes

(Full funding available for UK and EU applicants; others can apply if they wish)

References

Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I
Chouchani, E.T, Methner, C., Nadtochiy, S.M., Logan, A., Pell, V.R., Ding, S., James, A.M., Cochemé, H.M., Reinhold, J., Lilley, K.S., Partridge, L., Fearnley, I.M., Robinson, A.J., Hartley, R.C., Smith, R.A.J., Krieg, T., Brookes, P.S. & Murphy, M. P. Nature Med. (2013) 19 753-759.

A ratiometric fluorescent probe for assessing mitochondrial phospholipid peroxidation within living cells
Prime, T.A., Forkink, M., Logan, A., Finichiu, P., McLachlan, J., Pun, P.B.L., Koopman, W.J.H., Larsen, L., Latter, M.J., Robin A.J. Smith, R.A.J. & Murphy, M.P. Free Rad. Biol. Med. (2012) 53 544-553.

Mitochondrial pharmacology
Smith, R.A.J., Hartley, R.C., Cochemé, H.M. & Murphy, M. P. Trends Pharm. Sci. (2012) 33 341-352

Selective uncoupling of individual mitochondria within a cell using a mitochondria-targeted photoactivated protonophore
Chalmers, S., Caldwell, S., Quin, C., Prime, T. A., James, A. M., Cairns, A., Murphy, M.P., John McCarron, J. & Hartley, R. C. J.Am.Chem.Soc. (2012) 134 758-761

Using the mitochondria-targeted ratiometric mass spectrometry probe MitoB to measure H2O2 within living Drosophila
Cochemé, H.M., Logan, A., Prime, T. A., Abakumova, I., Quin, C., McQuaker, S.J., Patel, J.V., Fearnley, I.M., Smith, R.A.J., Hartley, R.C., Partridge, L. & Murphy, M.P. Nat. Prot. (2012) 7 946-958.

Mitochondria-targeted small molecule therapeutics and probes
Smith, R.A.J., Hartley, R.C. & Murphy, M.P.. Antioxid Redox Signall (2011) 15 3021-3038.

Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix
Cochemé, H.M., Quin, C., 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. Cell Metabolism (2011) 13 340-350.

The mitochondria-targeted antioxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients
Gane, E.J., Weilert, F., Orr, D.W., Keogh, G.F., Gibson, M., Lockhart, M.M., Frampton, C.M., Taylor, K.M., Smith, R.A.J. & Murphy, M.P. Liver Int. (2010) 30 1019-1026.

A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols and protects against ischemia-reperfusion injury
Prime, T.A., Blaikie, F.H., Evans, C., Nadtochiy, S.M., James, A.M., Dahm, C.C., Vitturi, D.A., Robin Hiley, C.R., Abakumova, I., Requejo, R., Chouchani, E.T., Hurd, T.R., Garvey, J.F., Taylor, C.T., Brookes, P.S., Smith, R.A.J. & Murphy, M.P. Proc. Natl. Acad. Sci. USA (2009) 106 10764-10769.




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