Abstract
The intraerythrocytic malaria parasite is susceptible to oxidative stress and this may play a role in the mechanism of action of some antimalarial agents. Here we show that exposure of the intraerythrocytic malaria parasite to the oxidising agent hydrogen peroxide results in a fall in the intracellular ATP level and inhibition of the parasite's V-type H+-ATPase, causing a loss of pH control in both the parasite cytosol and the internal digestive vacuole. In contrast to the V-type H+-ATPase, the parasite's digestive vacuole H+-pyrophosphatase is insensitive to hydrogen peroxide-induced oxidative stress. This work provides insights into the effects of oxidative stress on the intraerythrocytic parasite, as well as providing an alternative possible explanation for a previous report that light-induced oxidative stress causes selective lysis of the parasite's digestive vacuole.
Highlights
As it grows within its host erythrocyte, the unicellular malaria parasite is exposed to oxidative stress [1]
In this study we have shown that the oxidising agent H2O2, at concentrations comparable to those to which the parasite may be exposed in vivo ([35] cited in [4]), causes a decrease in parasite ATP levels and a profound disruption of intracellular pH regulation: an acidification of the parasite cytosol and an alkalinisation of the digestive vacuole (DV)
Generation of ATP in the intraerythrocytic malaria parasite is thought to be wholly via glycolysis [36], and compounds that inhibit glycolysis [28] or that inhibit glucose uptake into the parasites [37] induce a rapid decrease in parasite [ATP]i [38] and a cessation of parasite growth [28]
Summary
As it grows within its host erythrocyte, the unicellular malaria parasite is exposed to oxidative stress [1]. Haemoglobin in the host erythrocyte cytosol undergoes autoxidation to methaemoglobin, resulting in the generation of reactive oxygen radicals (O22) [2]. The parasite has a range of antioxidant defence mechanisms. It uses the reducing activity of two thiol-containing compounds, glutathione and thioredoxin, to combat oxidative agents such as H2O2 and superoxide (reviewed in [6]). Lacking the enzymes catalase and glutathione peroxidase, the parasite encodes a range of peroxiredoxins, which are used to detoxify oxygen radicals [7], and there is evidence that the intraerythrocytic parasite imports the human peroxiredoxin 2 from the host cell for the purpose of detoxifying peroxides [8]
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