Trypanosoma cruzi infection disturbs mitochondrial membrane potential and ROS production rate in cardiomyocytes

Gupta, Shivali; Bhatia, Vandanajay; Wen, Julie; Wu, Yuhong; Huang, Ming He; Garg, Nisha

doi:10.1016/j.freeradbiomed.2009.08.008

Cited by 112 publications

(111 citation statements)

References 41 publications

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“…This study suggested that Ca 2ϩ uptake and mitochondrial ROS production might be the early signaling events in the activation of PARP-1. 109 Recent studies 115 in an in vitro model of cardiomyocyte infection by T. cruzi support the previously described notion because we found that invasion by parasites triggered MPT and loss of membrane potential, which resulted in an inefficiency of the electron transport chain and increased ROS production. The ROS-induced DNA damage elicited PARP-1 activation; the latter, in turn, led to an increased formation of PARs.…”

Section: Parp-1-related Signaling Pathwayssupporting

confidence: 88%

Signaling Mechanism of Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Inflammatory Diseases

Garg

2011

The American Journal of Pathology

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171

140

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Poly(ADP-ribosyl)ation, attaching the ADP-ribose polymer chain to the receptor protein, is a unique posttranslational modification. Poly(ADP-ribose) polymerase-1 (PARP-1) is a well-characterized member of the PARP family. In this review, we provide a general update on molecular structure and structure-based activity of this enzyme. However, we mainly focus on the roles of PARP-1 in inflammatory diseases. Specifically, we discuss the signaling pathway context that PARP-1 is involved in to regulate the pathogenesis of inflammation. PARP-1 facilitates diverse inflammatory responses by promoting inflammation-relevant gene expression, such as cytokines, oxidation-reductionrelated enzymes, and adhesion molecules. Excessive activation of PARP-1 induces mitochondria-associated cell death in injured tissues and constitutes another mechanism for exacerbating inflammation. There are many posttranslational protein modifications (eg, phosphorylation, acetylation, methylation, and ubiquitylation) that are involved in a wide scope of cellular processes, including chromatin remodeling, transcriptional regulation, and signal transmission response to extracellular stimulation. Poly(ADP-ribosyl)ation (PARylation) is one of such essential protein modifications, whereby polymers of ADP-ribose (PARs) are formed from donor NAD ϩ molecules and covalently attached via an ester linkage to glutamic acid and less commonly to aspartic acid or lysine of target proteins.1-3 The target proteins generally contain a PAR-binding consensus motif that frequently overlaps with a functional domain, such as a protein-or DNA-binding domain (DBD), and thus accounts for PAR modification, altering the functional properties of the targets. 4 The process of PARylation is catalyzed by the poly-(ADP-ribose) polymerase (PARP) family of enzymes that consists of 18 members. 5 The PARPs, historically known as poly(ADP-ribose) synthases and poly(ADP-ribose) transferases, 6,7 show different structure, cellular location, and functions. 8,9 Only two members of this family (ie, PARP-1 and PARP-2) are DNA damage related; and PARP-1, the best-understood member, is an abundant nuclear enzyme and accounts for at least 85% of the cellular PARP activity. 10Since the discovery of PAR synthesis and PARP-1 decades ago, 11,12 new discoveries have been consistently published related to their structure, property, and functions. PARP-1 is a multifunctional enzyme and has a key role in the spatial and temporal organization of DNA repair, thus maintaining genome integrity and facilitating cell survival. PARP-1 catalyzes the synthesis and attachment of highly negatively charged PARs to target proteins, including histones, topoisomerases, DNA helicases, and single-strand break repair and base excision repair factors; and facilitates relaxation of the chromatin superstructure, protein-protein interaction, and DNAbinding ability of the members of the DNA repair machinery. A recently published article 13 reviews the role of PARP-1 in DNA repair. In addition, the importance of poly-(ADP-...

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Section: Parp-1-related Signaling Pathwayssupporting

confidence: 88%

Signaling Mechanism of Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Inflammatory Diseases

Garg

2011

The American Journal of Pathology

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“…Finally, the infectivity of TcAPx-CcP overexpressers was evaluated in cardiomyocytes, cells where amastigotes can reside during chronic infection. It has been shown that T. cruzi cardiomyocyte infection leads to the establishment of host-mitochondrial dysfunction, with an increase in H 2 O 2 and inflammatory cytokine (IL-1β and TNF-α) production (39). We evaluated the infectivity of TcAPx-CcP overexpressers following 96 h of infection, an incubation time sufficient to cause mitochondrial dysfunction in cardiomyocytes and to achieve amastigote replication in the host cell cytoplasm.…”

Section: Enhanced Virulence Of Tcapx-ccp Overexpressers In Cellular Amentioning

confidence: 99%

Kinetics, subcellular localization, and contribution to parasite virulence of a Trypanosoma cruzi hybrid type A heme peroxidase ( Tc APx-CcP)

Hugo

Martínez

Trujillo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The Trypanosoma cruzi ascorbate peroxidase is, by sequence analysis, a hybrid type A member of class I heme peroxidases [TcAPx-cytochrome c peroxidase (CcP)], suggesting both ascorbate (Asc) and cytochrome c (Cc) peroxidase activity. Here, we show that the enzyme reacts fast with H 2 O 2 (k = 2.9 × 10 7 M −1 ·s −1 ) and catalytically decomposes H 2 O 2 using Cc as the reducing substrate with higher efficiency than Asc (k cat /K m = 2.1 × 10 5 versus 3.5 × 10 4 M −1 ·s −1 , respectively). Visible-absorption spectra of purified recombinant TcAPx-CcP after H 2 O 2 reaction denote the formation of a compound I-like product, characteristic of the generation of a tryptophanyl radical-cation (Trp 233•+ ). Mutation of Trp 233 to phenylalanine (W233F) completely abolishes the Cc-dependent peroxidase activity. In addition to Trp 233•+ , a Cys 222 -derived radical was identified by electron paramagnetic resonance spin trapping, immunospin trapping, and MS analysis after equimolar H 2 O 2 addition, supporting an alternative electron transfer (ET) pathway from the heme. Molecular dynamics studies revealed that ET between Trp 233 and Cys 222 is possible and likely to participate in the catalytic cycle. Recognizing the ability of TcAPx-CcP to use alternative reducing substrates, we searched for its subcellular localization in the infective parasite stages (intracellular amastigotes and extracellular trypomastigotes). TcAPx-CcP was found closely associated with mitochondrial membranes and, most interestingly, with the outer leaflet of the plasma membrane, suggesting a role at the host-parasite interface. TcAPx-CcP overexpressers were significantly more infective to macrophages and cardiomyocytes, as well as in the mouse model of Chagas disease, supporting the involvement of TcAPx-CcP in pathogen virulence as part of the parasite antioxidant armamentarium.Trypanosoma cruzi | heme peroxidase | oxidants | virulence | kinetics

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“…Trypanosoma cruzi, the causative agent of Chagas disease, infects cardiomyocytes, alters their mitochondrial potential, and induces ROS (1). This overwhelms the antioxidant defenses and produces persistent oxidative stress (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress fuels Trypanosoma cruzi infection in mice

Paiva¹,

Feijó²,

Dutra³

et al. 2012

J. Clin. Invest.

150

175

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Trypanosoma cruzi infection disturbs mitochondrial membrane potential and ROS production rate in cardiomyocytes

Cited by 112 publications

References 41 publications

Signaling Mechanism of Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Inflammatory Diseases

Signaling Mechanism of Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Inflammatory Diseases

Kinetics, subcellular localization, and contribution to parasite virulence of a Trypanosoma cruzi hybrid type A heme peroxidase ( Tc APx-CcP)

Oxidative stress fuels Trypanosoma cruzi infection in mice

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