A homolog of cyclophilin D is expressed in Trypanosoma cruzi and is involved in the oxidative stress–damage response

Bustos, Patricia Laura; Volta, Bibiana Julieta; Perrone, Alina E.; Milduberger, Natalia; Búa, Jacqueline

doi:10.1038/cddiscovery.2016.92

Cited by 17 publications

(7 citation statements)

References 31 publications

(47 reference statements)

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“…In T. cruzi , the participation of mitochondrial cyclophilin as a component of this permeability pore was previously demonstrated. Incubation with hydrogen peroxide led to a loss of mitochondrial membrane potential and probably subsequent extensive lipid peroxidation in the parasite 137 . Depending on the ROS levels produced, protozoa lysis and consequent necrosis will occur.…”

Section: Death Processes In Trypanosomatidsmentioning

confidence: 99%

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

Menna-Barreto

2019

Cell Death Dis

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Especially in tropical and developing countries, the clinically relevant protozoa Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (sleeping sickness) and Leishmania species (leishmaniasis) stand out and infect millions of people worldwide leading to critical social-economic implications. Low-income populations are mainly affected by these three illnesses that are neglected by the pharmaceutical industry. Current anti-trypanosomatid drugs present variable efficacy with remarkable side effects that almost lead to treatment discontinuation, justifying a continuous search for alternative compounds that interfere with essential and specific parasite pathways. In this scenario, the triggering of trypanosomatid cell death machinery emerges as a promising approach, although the exact mechanisms involved in unicellular eukaryotes are still unclear as well as the controversial biological importance of programmed cell death (PCD). In this review, the mechanisms of autophagy, apoptosis-like cell death and necrosis found in pathogenic trypanosomatids are discussed, as well as their roles in successful infection. Based on the published genomic and proteomic maps, the panel of trypanosomatid cell death molecules was constructed under different experimental conditions. The lack of PCD molecular regulators and executioners in these parasites up to now has led to cell death being classified as an unregulated process or incidental necrosis, despite all morphological evidence published. In this context, the participation of metacaspases in PCD was also not described, and these proteases play a crucial role in proliferation and differentiation processes. On the other hand, autophagic phenotype has been described in trypanosomatids under a great variety of stress conditions (drugs, starvation, among others) suggesting that this process is involved in the turnover of damaged structures in the protozoa and is not a cell death pathway. Death mechanisms of pathogenic trypanosomatids may be involved in pathogenesis, and the identification of parasite-specific regulators could represent a rational and attractive alternative target for drug development for these neglected diseases.

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Section: Death Processes In Trypanosomatidsmentioning

confidence: 99%

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

Menna-Barreto

2019

Cell Death Dis

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“…66,67 NiNPs uptake by mitochondria may be behind elevated oxidative stress, since mitochondria play a crucial role in cellular oxidative stress. 68,69 Recently, other NPs such as silica NPs, were found to induce oxidative stress causing impaired mitochondrial function leading to apoptosis. 67 NiNPs-induced oxidative stress has been suggested to cause nanotoxicity, particularly induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

<p>Internalization and effects on cellular ultrastructure of nickel nanoparticles in rat kidneys</p>

Abdulqadir¹,

Aziz²

2019

IJN

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Purpose: Since nanoparticles (NPs) are beginning to be introduced in medicine and industry, it is mendatory to evaluate their biological side-effects, among other things. The present study aimed to investigate the pathways by which nickel nanoparticles (NiNPs) enter nephrons and to evaluate their localization and effects on cellular ultrastructure. Methods: Rats were injected intraperitoneally with 20 nm NiNPs (20 mg/Kg/b.w./day) for 28 consecutive days. Transmission electron microscope technique was used to detect localization of NiNPs and their effects on cellular ultrastructure in rat kidneys. Additionally, measurements of certain biochemical parameters such as creatinine, urea, uric acid and phosphorus for investigating renal function following NiNPs treatment were taken. Results: The presence of NiNPs in the nephrons in treated rats was confirmed by transmission electron microscopy. NiNPs entered the renal tubules cells via various pathways. The results indicated that NiNPs administration induced ultrastructural changes in the proximal cells of renal tubules and certain glomerular cells (podocytes and mesangial cells). Additionally, NiNPs were found to be localized in the mitochondria, which led to a significant decrease in their density and morphology. Furthermore, cell death was induced in the glomerular cells as found with a Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assay and through detection of p35 using immunohistochemical staining. Conclusion: Herein, NiNPs were found to induce various cellular ultrastructural changes in the kidneys of rats. NiNPs used diverse pathways to internalize into the cytoplasm of the proximal convoluted tubules (PT) cells across the basement membrane, and also through the plasma membrane of two adjacent PT cells. NiNPs internalization, accumulation and their alterations of the cellular ultrastructure affected rat renal function.

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“…Regarding the CsA cytoprotective effects observed in T. cruzi that undergo oxidative stress, we proposed the existence of a mitochondrial transition pore-like in the parasite, and searched for an homologue of the mammalian CyPD in the parasite as target. Tc CyP22 protein, which could be isolated by CsA affinity chromatography [17], showed a putative mitochondrial localization, and its localization to mitochondria was confirmed in the three stages of the parasite life cycle [52]. Oxidative stress was induced in overexpressing Tc CyP22 parasites and an enhanced loss of mitochondrial membrane potential and cell viability were significantly different from control parasites, defining an homologue of CyPD for the first time in a protozoan parasite, and the involvement of this protein in T. cruzi regulated cell death [52,53].…”

Section: Functional Features Of T Cruzi Peptidyl-prolyl Cis-transmentioning

confidence: 99%

A Functional Analysis of the Cyclophilin Repertoire in the Protozoan Parasite Trypanosoma Cruzi

et al. 2018

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Trypanosoma cruzi is the etiological agent of Chagas disease. It affects eight million people worldwide and can be spread by several routes, such as vectorborne transmission in endemic areas and congenitally, and is also important in non-endemic regions such as the United States and Europe due to migration from Latin America. Cyclophilins (CyPs) are proteins with enzymatic peptidyl-prolyl isomerase activity (PPIase), essential for protein folding in vivo. Cyclosporin A (CsA) has a high binding affinity for CyPs and inhibits their PPIase activity. CsA has proved to be a parasiticidal drug on some protozoa, including T. cruzi. In this review, we describe the T. cruzi cyclophilin gene family, that comprises 15 paralogues. Among the proteins isolated by CsA-affinity chromatography, we found orthologues of mammalian CyPs. TcCyP19, as the human CyPA, is secreted to the extracellular environment by all parasite stages and could be part of a complex interplay involving the parasite and the host cell. TcCyP22, an orthologue of mitochondrial CyPD, is involved in the regulation of parasite cell death. Our findings on T. cruzi cyclophilins will allow further characterization of these processes, leading to new insights into the biology, the evolution of metabolic pathways, and novel targets for anti-T. cruzi control.

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A homolog of cyclophilin D is expressed in Trypanosoma cruzi and is involved in the oxidative stress–damage response

Cited by 17 publications

References 31 publications

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

<p>Internalization and effects on cellular ultrastructure of nickel nanoparticles in rat kidneys</p>

A Functional Analysis of the Cyclophilin Repertoire in the Protozoan Parasite Trypanosoma Cruzi

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