O2 consumption rates along the growth curve: new insights into Trypanosoma cruzi mitochondrial respiratory chain

Silva, Thiago M.; Peloso, E.F.; Vitor, Simone Cespedes; Ribeiro, Luis Henrique Leandro; Gadelha, Fernanda Ramos

doi:10.1007/s10863-011-9369-0

Cited by 25 publications

(27 citation statements)

References 43 publications

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“…The mitochondrion represents the most recurrent target, and the intensity of the alterations in this organelle is time dependent and varies with the compound employed [30, 104, 105]. Numerous articles point to the mitochondrion as a drug target in trypanosomatids, primarily based on transmission electron microscopy analysis and MMP evaluation using flow cytometry [29, 83, 106, 107].…”

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

107

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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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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

107

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“…However, recent finding demonstrate that complex I of the respiratory chain has limited functions in T . cruzi metabolism [ 12 , 13 ]. Moreover, succinate has been shown to be the main substrate that supports oxygen consumption in epimastigotes [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Gallate Triphenylphosphonium Derivatives with Potent Antichagasic Activity

et al. 2015

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Chagas disease is one of the most neglected tropical diseases in the world, affecting nearly 15 million people, primarily in Latin America. Only two drugs are used for the treatment of this disease, nifurtimox and benznidazole. These drugs have limited efficacy and frequently induce adverse effects, limiting their usefulness. Consequently, new drugs must be found. In this study, we demonstrated the in vitro trypanocidal effects of a series of four gallic acid derivatives characterized by a gallate group linked to a triphenylphosphonium (TPP+) moiety (a delocalized cation) via a hydrocarbon chain of 8, 10, 11, or 12 atoms (TPP+-C8, TPP+-C10, TPP+-C11, and TPP+-C12, respectively). We analyzed parasite viability in isolated parasites (by MTT reduction and flow cytometry) and infected mammalian cells using T. cruzi Y strain trypomastigotes. Among the four derivatives, TPP+-C10 and TPP+-C12 were the most potent in both models, with EC50 values (in isolated parasites) of 1.0 ± 0.6 and 1.0 ± 0.7 μM, respectively, and were significantly more potent than nifurtimox (EC50 = 4.1 ± 0.6 μM). At 1 μM, TPP+-C10 and TPP+-C12 induced markers of cell death, such as phosphatidylserine exposure and propidium iodide permeabilization. In addition, at 1 μM, TPP+-C10 and TPP+-C12 significantly decreased the number of intracellular amastigotes (TPP+-C10: 24.3%, TPP+-C12: 19.0% of control measurements, as measured by DAPI staining) and the parasite’s DNA load (C10: 10%, C12: 13% of control measurements, as measured by qPCR). Based on the previous mode of action described for these compounds in cancer cells, we explored their mitochondrial effects in isolated trypomastigotes. TPP+-C10 and TPP+-C12 were the most potent compounds, significantly altering mitochondrial membrane potential at 1 μM (measured by JC-1 fluorescence) and inducing mitochondrial transition pore opening at 5 μM. Taken together, these results indicate that the TPP+-C10 and TPP+-C12 derivatives of gallic acid are promising trypanocidal agents with mitochondrial activity.

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“…All infected cultures, containing intracellular parasites, were maintained in DMEM low-glucose media (Sigma-Aldrich), supplemented as described for mammalian cells, but with 2 % FBS [41]. T. cruzi epimastigotes (Y strain) were kindly provided by Dr Maria Júlia Manso Alves (Chemistry Institute-University of São Paulo) and were grown in liver infusion tryptose medium supplemented with 20 mg/L hemin and 10 % fetal calf serum at 28°C [42]. L. amazonensis strain MHOM/BR/1973/M2269 was kindly provided by Dr Silvia Uliana (Biomedical Sciences Institute-University of São Paulo).…”

Section: In Vitro Cell Culturementioning

confidence: 99%

“…Respiratory control ratio (state 3/state 4) was determined by the addition of 400 µM ADP (state 3) followed by 2 µg/mL oligomycin (state 4). Maximum oxygen consumption rates were determined in the presence of 1 µM carbonyl cyanide m-chlorophenylhydrazone [42].…”

Section: Antileishmanial and Antitrypanosomal Activity Assaysmentioning

confidence: 99%

Prospecting and Identifying Phyllanthus amarus Lignans with Antileishmanial and Antitrypanosomal Activity

et al. 2020

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Ten lignans (1 – 10) were isolated from the hexane-ethyl acetate extract of Phyllanthus amarus leaves. Three of them, cubebin dimethyl ether (3), urinatetralin (4), and lintetralin (7) are described for the first time in this species, while phyllanthin (1), niranthin (2), 5-demethoxyniranthin (5), isolintetralin (6), hypophyllanthin (8), nirtetralin (9), and phyltetralin (10) have been already reported from P. amarus. Among the lignans tested against Trypanosoma cruzi intracellular amastigotes, 2 was the most active with an EC50 of 35.28 µM. Lignans 2, 5, 7, and 9 showed inhibitory effects against Leishmania amazonensis promastigotes with EC50 of 56.34, 51.86, 23.57, and 43.27 µM, respectively. During in vitro infection assays, 5 reduced amastigotes by 91% at 103.68 µM concentration, whereas 7 and 9 reduced amastigotes by approximately 84% at 47.5 and 86.04 µM, respectively. Lignans 5, 7, and 9 were more potent in intracellular amastigotes with EC50 of 2.76, 8.30, and 15.83 µM, respectively, than in promastigotes. CC50 for all samples was > 100 µg/mL, thus revealing low cytotoxicity against macrophages, and selectivity against the parasite. L. amazonensis promastigotes treated with compounds 2 and 9 showed decreased respiratory control of 38% and 25%, respectively, suggesting a change in mitochondrial membrane potential and lower ATP production.

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O2 consumption rates along the growth curve: new insights into Trypanosoma cruzi mitochondrial respiratory chain

Cited by 25 publications

References 43 publications

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

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

Novel Gallate Triphenylphosphonium Derivatives with Potent Antichagasic Activity

Prospecting and Identifying Phyllanthus amarus Lignans with Antileishmanial and Antitrypanosomal Activity

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