Professor Mark Hampton; Mātai Hāora - Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
Life in oxygen is associated with the generation of damaging reactive oxygen species. Cells have sensitive signalling pathways that enable them to respond to external and internal oxidative stress, and they also appear to generate oxidants as signalling molecules that exploit similar pathways. Signal transmission occurs via oxidation of specific cysteine residues in regulatory proteins, and while oxidation is typically transient, it can lead to more sustained alterations in gene expression through the modulation of transcription factors and epigenetic regulators.
Diseases associated with sustained oxidative stress can perturb redox signalling pathways, but traditional antioxidants struggle to protect sensitive targets from oxidation. There is evidence that redox signalling is controlled by a family of thiol peroxidases called peroxiredoxins. These proteins are exquisitely sensitive to reversible oxidation by hydrogen peroxide. While peroxidase activity is mediated by dimers, peroxiredoxins form complex decameric rings. These rings can be scaffolds for enabling the interaction of peroxiredoxins with specific intracellular targets. Signal transduction may occur through facilitated oxidation, or through altered protein-protein interactions. We are using molecular and pharmacological tools to disrupt peroxiredoxin protein interactions inside cells. In the first instance these tools will be useful for dissecting redox signalling pathways. Ultimately, they may provide new strategies for protecting cells from pathological oxidative stress.
Peroxiredoxins are also useful reporters of disrupted cellular redox homeostasis. Our recent focus has been the biology of ageing. Using blood samples from participants in the longitudinal Dunedin Study, we have observed increased levels of oxidative and mitochondrial stress in faster ageing people at midlife, prior to the onset of age-related disease.
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