Cellular targets of the myeloperoxidase-derived oxidant hypothiocyanous acid (HOSCN) and its role in the inhibition of glycolysis in macrophages

D Love, T.J. Barrett, M.Y. White, S.J. Cordwell, Michael Jonathan Davies, Clare Louise Hawkins

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Abstract

Myeloperoxidase (MPO) released at sites of inflammation catalyzes the formation of the oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) from H2O2 and halide and pseudo-halide ions. HOCl, a major oxidant produced under physiological conditions reacts rapidly with many biological molecules, and is strongly linked with tissue damage during inflammatory disease. The role of HOSCN in disease is less clear, though it can initiate cellular damage by pathways involving the selective oxidation of thiol-containing proteins. Utilizing a thiol-specific proteomic approach, we explored the cellular targets
of HOSCN in macrophages (J774A.1). We report that multiple thiol-containing proteins involved in metabolism and glycolysis; fructose bisphosphate aldolase, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and creatine kinase, together with a number of chaperone, antioxidant
and structural proteins, were modified in a reversible manner in macrophages treated with HOSCN. The modification of the metabolic enzymes was associated with a decrease in basal glycolysis, glycolytic reserve, glycolytic capacity and lactate release, which was only partly reversible on further incubation in the absence of HOSCN. Inhibition of glycolysis preceded cell death and was seen in cells exposed to low concentrations (r25 mM) of HOSCN. The ability of HOSCN to inhibit glycolysis and perturb energy production is likely to contribute to the cell death seen in macrophages on further incubation after the initial treatment period, which may be relevant for the propagation of inflammatory disease in smokers, who have elevated plasma levels of the HOSCN precursor, thiocyanate.
Original languageEnglish
JournalFree Radical Biology & Medicine
Volume94
Pages (from-to)88-98
Number of pages11
ISSN0891-5849
DOIs
Publication statusPublished - 2016

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