Biochemistry

Research in our lab is aimed at understanding the regulation of signal transduction in mammalian cells. We are currently focusing on two specific pathways; the role of cytochrome c in the regulation of apoptosis, and redox regulation of mammalian cell signalling.

Determining the role of cytochrome c in the regulation of apoptosis

Redox regulation of mammalian cell signalling

Oxidants and free radicals have historically been considered harmful, causing damage to cells and being associated with disease. However over recent years it has become apparent that reactive oxygen species and shifts in redox equilibria can have beneficial as well as detrimental effects in cells. We are interested in understanding how alterations in redox equilibria translate into cellular outcomes. Hydrogen peroxide is a particularly important oxidant in cell signalling, and our data suggests that the peroxiredoxin family of peroxidases has an active role in converting peroxides into useful signals in mammalian cells, by catalysing disulfide bond formation in target proteins. The function and regulation of peroxiredoxins, and other antioxidant enzymes, is being investigated using inducible overexpression and knockdown of enzymes involved in the metabolism of reactive oxygen species (ROS) and analysing specific signalling pathways. 

Positions available

Enquires about projects from prospective graduate students and postdoctoral fellows are welcome.

Information about scholarships for New Zealand postgraduate students go to the University of Otago's website - Postgraduate & Scholarship Awards.
University of Otago's website for information about funding for International Students.

Selected Publications

Liptak, M.D., Fagerlund, R.D., Ledgerwood, E.C., Wilbanks, S.M. and Bren, K.L. The proapoptotic G41S mutation to human cytochrome c alters the heme electronic structure and increases the electron self-exchange rate Journal of the American Chemical Society 133, 1153-1155 (2011)

Porteous, C.M., Logan, A., Evans, C., Ledgerwood, E.C., Menon, D.K., Aigbirhio, F., Smith, A.J. and Murphy, M.P. Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: Implications for mitochondria-specific therapies and probes Biochim Biophys Acta 1800, 1009-1017 (2010)

Westphal, D., Ledgerwood, E.C.#, Tyndall, J.D., Hibma, M.H., Ueda, N., Fleming, S.B. and Mercer, A.# The orf virus inhibitor of apoptosis functions in a Bcl-2-like manner, binding and neutralizing a set of BH3-only proteins and active Bax. Apoptosis 14, 1317-1330 (2009)  (#joint senior authors)

Ledgerwood, E.C. and Morison, I.M. Targeting the apoptosome for cancer therapy. Clinical Cancer Research 15, 420-424 (2009)

Morison, I.M., Cramer-Bordé, E.M., Cheesman, E.J., Cheong, P.L., Holyoake, A.J., Fichelson, S., Weeks, R.J., Lo, A., Davies, S.M.K., Wilbanks, S.M., Fagerlund, R.D., Ludgate, M.W., da Silva Tatley, F.M., Coker, M.S.A., Bockett, N.A., Hughes, G., Pippig, D.A., Smith, M.P., Capron, C. and Ledgerwood, E.C. A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nature Genetics 40, 387-389 (2008)

Cox, A. G., Pullar, J. M., Hughes, G., Ledgerwood, E. C. and Hampton, M. B. Oxidation of mitochondrial peroxiredoxin 3 during the initiation of receptor-mediated apoptosis. Free Radical Biology and Medicine, 44: 1001-1009 (2008)

Jarvis, R.M., Göttert, J., Murphy, M.P. and Ledgerwood, E.C. Mitochondria-targeted antioxidants do not prevent tumour necrosis factor-induced necrosis of L929 cells Free Radical Research 41, 1041-1046 (2007)

Westphal, D., Ledgerwood, E.C., Hibma, M.H., Fleming, S.B., Whelan, E.M. and Mercer, A.A. A novel Bcl-2-like inhibitor of apoptosis is encoded by the parapoxvirus, Orf virus.  Journal of Virology 81, 7178-7188 (2007)

Hughes, G., Murphy, M.P. and Ledgerwood, E.C. Mitochondrial reactive oxygen species regulate the temporal activation of Nuclear Factor kappa B to modulate Tumour Necrosis Factor-induced apoptosis: evidence from mitochondria-targeted antioxidants. Biochemical Journal 389, 83-89 (2005)

Kelso, G.F., Porteous, C.M., Hughes, G., Ledgerwood, E.C., Gane, A.M., Smith, R.A.J. and Murphy, M.P.  Prevention of Mitochondrial Oxidative Damage Using Targeted Antioxidants. Annals of the New York Academy of Sciences, 959, 263-274 (2002)

Kelso, G.F., Porteous, C.M., Coulter, C.V., Hughes, G., Porteous, W.K., Ledgerwood, E.C., Smith, R.A.J. and Murphy, M.P.  Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. Journal of Biological Chemistry, 276, 4588–4596 (2001)

Scarlett, J.L., Sheard, P.W., Hughes, G., Ledgerwood, E.C., Ku, H-H. and Murphy, M.P. Changes in mitochondrial membrane potential during staurosporine-induced apoptosis in Jurkat cells. FEBS Letters, 475, 267-272 (2000)