title: Oxidative stress generated during monensin treatment contributes to altered Toxoplasma gondii mitochondrial function.
abstract: The ionophore monensin displays potent activities against several coccidian parasites of veterinary and medical importance including the opportunistic pathogen of humans, Toxoplasma gondii. While monensin is used widely in animals, toxicity impedes its use in humans. Nonetheless, given its potency, understanding its mode of action would reveal vulnerable aspects of the parasite that can be exploited for drug development. We previously established that monensin induces Toxoplasma to undergo cell cycle arrest and an autophagy-like cell death. Interestingly, these effects are dependent on the mitochondrion-localized TgMSH-1 protein, suggesting that monensin disrupts mitochondrial function. We demonstrate that monensin treatment results in decreased mitochondrial membrane potential and altered morphology. These effects are mitigated by the antioxidant compound N-acetyl-cysteine suggesting that monensin causes an oxidative stress, which was indeed the case based on direct detection of reactive oxygen species. Moreover, over-expression of the antioxidant proteins glutaredoxin and peroxiredoxin 2 protect Toxoplasma from the deleterious effects of monensin. Thus, our studies show that the effects of monensin on Toxoplasma are due to a disruption of mitochondrial function caused by the induction of an oxidative stress and implicate parasite redox biology as a viable target for the development of drugs against Toxoplasma and related pathogenic parasites.
authors.affiliation: Departments of Pharmacology and Toxicology Indiana University School of Medicine, Indianapolis, Indiana 46202, US.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Charvat
authors.affiliation: Departments of Pharmacology and Toxicology Indiana University School of Medicine, Indianapolis, Indiana 46202, US.|Departments of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, US.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Arrizabalaga
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000469:parasitology; D052816:Foreskin / Q000166:cytology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008985:Monensin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D061209:Proton Ionophores / Q000494:pharmacology; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014122:Toxoplasma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D054477:Glutaredoxins; D061209:Proton Ionophores; D015800:Protozoan Proteins; D008985:Monensin; D054464:Peroxiredoxins; D000111:Acetylcysteine