The Uniqueness of the Trypanosoma cruzi Mitochondrion: Opportunities to Target New Drugs Against Chagas Disease

Paes, Lisvane Silva; Mantilla, Brian S.; Barisón, María Julia; Wrenger, Carsten; Silber, Ariel Mariano

doi:10.2174/138161211796904786

Cited by 39 publications

(24 citation statements)

References 337 publications

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“…This paper demonstrates that the product of the TcPRODH gene is a FAD-dependent L-proline oxidoreductase, the first enzyme that catabolizes proline in T. cruzi [57], [58]. The specificity of TcPRODH was also evaluated and closely related analogues such as D-proline, hydroxyproline, L-pipecolic acid, nicotinic acid and thiazolidine-4-carboxylic acid (T4C), did not act as enzyme substrates.…”

Section: Discussionmentioning

confidence: 99%

Proline Dehydrogenase Regulates Redox State and Respiratory Metabolism in Trypanosoma cruzi

et al. 2013

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Over the past three decades, L-proline has become recognized as an important metabolite for trypanosomatids. It is involved in a number of key processes, including energy metabolism, resistance to oxidative and nutritional stress and osmoregulation. In addition, this amino acid supports critical parasite life cycle processes by acting as an energy source, thus enabling host-cell invasion by the parasite and subsequent parasite differentiation. In this paper, we demonstrate that L-proline is oxidized to Δ1-pyrroline-5-carboxylate (P5C) by the enzyme proline dehydrogenase (TcPRODH, E.C. 1.5.99.8) localized in Trypanosoma cruzi mitochondria. When expressed in its active form in Escherichia coli, TcPRODH exhibits a Km of 16.58±1.69 µM and a Vmax of 66±2 nmol/min mg. Furthermore, we demonstrate that TcPRODH is a FAD-dependent dimeric state protein. TcPRODH mRNA and protein expression are strongly upregulated in the intracellular epimastigote, a stage which requires an external supply of proline. In addition, when Saccharomyces cerevisiae null mutants for this gene (PUT1) were complemented with the TcPRODH gene, diminished free intracellular proline levels and an enhanced sensitivity to oxidative stress in comparison to the null mutant were observed, supporting the hypothesis that free proline accumulation constitutes a defense against oxidative imbalance. Finally, we show that proline oxidation increases cytochrome c oxidase activity in mitochondrial vesicles. Overall, these results demonstrate that TcPRODH is involved in proline-dependant cytoprotection during periods of oxidative imbalance and also shed light on the participation of proline in energy metabolism, which drives critical processes of the T. cruzi life cycle.

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Section: Discussionmentioning

confidence: 99%

Proline Dehydrogenase Regulates Redox State and Respiratory Metabolism in Trypanosoma cruzi

et al. 2013

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“…Furthermore, the contribution of the RNA editing process to mitochondrial functional plasticity cannot be excluded. Presently, this possibility should be considered as a hypothesis, and additional studies are needed for confirmation [152]. In this context, Liang and Connell [153] employed high-throughput screening to identify specific inhibitors of RNA editing.…”

Section: Mitochondria In Trypanosomatidsmentioning

confidence: 99%

The Double-Edged Sword in Pathogenic Trypanosomatids: The Pivotal Role of Mitochondria in Oxidative Stress and Bioenergetics

Menna-Barreto

Castro

2014

BioMed Research International

101

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The pathogenic trypanosomatids Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. are the causative agents of African trypanosomiasis, Chagas disease, and leishmaniasis, respectively. These diseases are considered to be neglected tropical illnesses that persist under conditions of poverty and are concentrated in impoverished populations in the developing world. Novel efficient and nontoxic drugs are urgently needed as substitutes for the currently limited chemotherapy. Trypanosomatids display a single mitochondrion with several peculiar features, such as the presence of different energetic and antioxidant enzymes and a specific arrangement of mitochondrial DNA (kinetoplast DNA). Due to mitochondrial differences between mammals and trypanosomatids, this organelle is an excellent candidate for drug intervention. Additionally, during trypanosomatids' life cycle, the shape and functional plasticity of their single mitochondrion undergo profound alterations, reflecting adaptation to different environments. In an uncoupling situation, the organelle produces high amounts of reactive oxygen species. However, these species role in parasite biology is still controversial, involving parasite death, cell signalling, or even proliferation. Novel perspectives on trypanosomatid-targeting chemotherapy could be developed based on better comprehension of mitochondrial oxidative regulation processes.

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“…Among these natural stresses, oxidative, nutritional, thermal and pH stress are relevant. Several vital mechanisms related to the ability of T. cruzi to cope with these conditions have been described [25]. The interference of LM with such mechanisms could be relevant to prospect an in vivo study of LM by itself or in combination with other drugs.…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate the possible interaction between both treatments, the parasites were incubated for 90 min with the IC 50 concentration of H 2 O 2 (0.10 mM) in PBS and further incubated in LIT medium supplemented or not with the IC 25 concentration of LM (0.25 mM). The combined treatment of LM and H 2 O 2 showed a statistically significant effect (p < 0.05), measured as a reduction in the capability of parasite to growth at day 5 post-treatment.…”

Section: Oxidative Stressmentioning

confidence: 99%

Evaluation of the Anti-<i>Trypanosoma Cruzi</i> Effects of the Antipsychotic Drug Levomepromazine

Lange¹,

Pral²,

Magdaleno³

et al. 2012

IJCM

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Chagas disease, caused by the protozoan Trypanosoma cruzi, is a relevant parasitic disease in the Americas. Current chemotherapy relies on Nifurtimox and Benznidazole, which present serious drawbacks, including high toxicity, low efficiency and the emergence of resistant strains. In the present work, the perspectives of levomepromazine, a tricyclic compound belonging to the family of phenotiazines with well-known properties as antipsychotics were evaluated as a potential anti-T. cruzi drug. We show that this drug is able to inhibit the proliferation of epimastigotes (IC 50 = 0.41 ± 0.01 mM) and to interfere with the infection of the host cells (IC 50 = 0.34 ± 0.01 mM). Interestingly, the treatment with levomepromazine affected the ability of metabolites such as glucose, proline and glutamate to fuel the recovery of epimastigotes after being submitted to metabolic stress. These findings prompt levomepromazine as a promising leader drug to obtain new trypanocidal activities.

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The Uniqueness of the Trypanosoma cruzi Mitochondrion: Opportunities to Target New Drugs Against Chagas Disease

Cited by 39 publications

References 337 publications

Proline Dehydrogenase Regulates Redox State and Respiratory Metabolism in Trypanosoma cruzi

Proline Dehydrogenase Regulates Redox State and Respiratory Metabolism in Trypanosoma cruzi

The Double-Edged Sword in Pathogenic Trypanosomatids: The Pivotal Role of Mitochondria in Oxidative Stress and Bioenergetics

Evaluation of the Anti-<i>Trypanosoma Cruzi</i> Effects of the Antipsychotic Drug Levomepromazine

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The Uniqueness of the Trypanosoma cruzi Mitochondrion: Opportunities to Target New Drugs Against Chagas Disease

Cited by 39 publications

References 337 publications

Proline Dehydrogenase Regulates Redox State and Respiratory Metabolism in Trypanosoma cruzi

Proline Dehydrogenase Regulates Redox State and Respiratory Metabolism in Trypanosoma cruzi

The Double-Edged Sword in Pathogenic Trypanosomatids: The Pivotal Role of Mitochondria in Oxidative Stress and Bioenergetics

Evaluation of the Anti-&lt;i&gt;Trypanosoma Cruzi&lt;/i&gt; Effects of the Antipsychotic Drug Levomepromazine

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Evaluation of the Anti-<i>Trypanosoma Cruzi</i> Effects of the Antipsychotic Drug Levomepromazine