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Contact Details

Phone
+64 3 479 5195
Email
liz.Ledgerwood@otago.ac.nz

University Links

Position
Associate Professor
Department
Department of Biochemistry
Qualifications
BSc(Hons), PhD
Research summary
Apoptosis, signal transduction, redox regulation

Research

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

In collaboration with Professor Ian Morison we have identified the first naturally occurring mutation in cytochrome c, in a New Zealand family with mild thrombocytopenia (low platelets). This mutation enhances the activity of cytochrome c in the cell death pathway. By dysregulating platelet production in the bone marrow, the mutant protein causes premature release of platelets into the marrow space instead of into the circulation. We are characterising the molecular basis of this increased activity, and determining how this alters platelet production.

Scientific image.
Crystal structure of human G41S cytochrome c.

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.

Scientific image.
Model for the function of peroxiredoxins.

Publications

Faiz, M., Kalev-Zylinska, M. L., Dunstan-Harrison, C., Singleton, D. C., Hay, M. P., & Ledgerwood, E. C. (2024). Megakaryocyte maturation involves activation of the adaptive unfolded protein response. Genes to Cells. Advance online publication. doi: 10.1111/gtc.13151 Journal - Research Article

Dunstan-Harrison, C., Morison, I. M., & Ledgerwood, E. C. (2024). Inherited thrombocytopenia associated with a variant in the FLI1 binding site in the 5' UTR of ANKRD26. Clinical Genetics. Advance online publication. doi: 10.1111/cge.14547 Journal - Research Article

Shafaei Pishabad, Z., & Ledgerwood, E. C. (2024). The Y49H cytochrome c variant enhances megakaryocytic maturation of K-562 cells. Biochimica et Biophysica Acta: Molecular Basis of Disease, 1870(5), 167134. doi: 10.1016/j.bbadis.2024.167134 Journal - Research Article

Chin, T. C., Wilbanks, S. M., & Ledgerwood, E. C. (2024). Altered conformational dynamics contribute to species-specific effects of cytochrome c mutations on caspase activation. Journal of Biological Inorganic Chemistry. Advance online publication. doi: 10.1007/s00775-024-02044-2 Journal - Research Article

Barzak, F. M., Lu, A., Geltzeiler, A. R., Ledgerwood, E. C., Chung, W. K., & Day, C. L. (2024). A novel RNF125 variant associated with Tenorio syndrome alters ubiquitin chain binding. Clinical Genetics, 105, 254-261. doi: 10.1111/cge.14457 Journal - Research Article

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