Oxidative stress generated during monensin treatment contributes to altered Toxoplasma gondii mitochondrial function
Robert A Charvat1, Gustavo Arrizabalaga1,2
1Departments of Pharmacology and Toxicology Indiana University School of Medicine, Indianapolis, Indiana 46202, US.
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.
Insights
Monensin disrupts mitochondria in Toxoplasma gondii, causing oxidative stress and cell death. Targeting parasite redox biology offers a new strategy for developing drugs against Toxoplasma and similar parasites.
Area of Science:
- Parasitology
- Molecular Biology
- Drug Discovery
Background:
- Monensin is a potent ionophore effective against coccidian parasites like Toxoplasma gondii.
- Toxicity limits monensin's use in humans, but its mechanism offers drug development insights.
- Previous work linked monensin to cell cycle arrest and autophagy-like death dependent on TgMSH-1.
Purpose of the Study:
- To elucidate the mechanism of monensin's action against Toxoplasma gondii.
- To investigate the role of mitochondrial dysfunction and oxidative stress in monensin's effects.
- To identify potential drug targets within parasite redox biology.
Main Methods:
- Assessed mitochondrial membrane potential and morphology changes in monensin-treated Toxoplasma.
- Utilized N-acetyl-cysteine to evaluate the role of oxidative stress.
- Over-expressed antioxidant proteins (glutaredoxin, peroxiredoxin 2) to assess protective effects.
- Detected reactive oxygen species (ROS) production directly.
Main Results:
- Monensin treatment decreased mitochondrial membrane potential and altered mitochondrial morphology.
- N-acetyl-cysteine mitigated monensin's effects, indicating oxidative stress.
- Direct ROS detection confirmed oxidative stress induction by monensin.
- Over-expression of antioxidant proteins conferred protection against monensin.
Conclusions:
- Monensin disrupts mitochondrial function in Toxoplasma gondii by inducing oxidative stress.
- Parasite redox biology is a promising target for developing new anti-Toxoplasma drugs.
- Understanding monensin's mechanism can guide the development of therapies against related parasitic infections.
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