Mitochondrial peroxiredoxin 3 is rapidly oxidized in cells treated with isothiocyanates

Brown, Kristin K.; Eriksson, Sofi; Arnér, Elias S.J.; Hampton, Mark B.

doi:10.1016/j.freeradbiomed.2008.04.030

Cited by 59 publications

(50 citation statements)

References 40 publications

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“…One possible explanation is that loss of the ability to reduce thioredoxin may have a broad impact on all thioredoxin-dependent targets, including mitochondrial perioxiredoxins other than PRX3, or Trx-dependent protein complexes that might impact ROS production or scavenging indirectly (34). Second, increased oxidative stress upon TXNRD2 knockdown could be further enhanced by hyperoxidation of PRX3, which is known to occur after treatment with auranofin, a thioredoxin reductase inhibitor, or other stressors (35)(36)(37)(38). This hyperoxidation results in inactivation of PRX3 (37).…”

Section: Discussionmentioning

confidence: 99%

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Dey

Sidor

O’Rourke

2016

Journal of Biological Chemistry

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Oxidative stress arises from an imbalance in the production and scavenging rates of reactive oxygen species (ROS) and is a key factor in the pathophysiology of cardiovascular disease and aging. The presence of parallel pathways and multiple intracellular compartments, each having its own ROS sources and antioxidant enzymes, complicates the determination of the most important regulatory nodes of the redox network. Here we quantified ROS dynamics within specific intracellular compartments in the cytosol and mitochondria and determined which scavenging enzymes exert the most control over antioxidant fluxes in H9c2 cardiac myoblasts. We used novel targeted viral gene transfer vectors expressing redox-sensitive GFP fused to sensor domains to measure H 2 O 2 or oxidized glutathione. Using genetic manipulation in heart-derived H9c2 cells, we explored the contribution of specific antioxidant enzymes to ROS scavenging and glutathione redox potential within each intracellular compartment. Our findings reveal that antioxidant flux is strongly dependent on mitochondrial substrate catabolism, with availability of NADPH as a major rate-controlling step. Moreover, ROS scavenging by mitochondria significantly contributes to cytoplasmic ROS handling. The findings provide fundamental information about the control of ROS scavenging by the redox network and suggest novel interventions for circumventing oxidative stress in cardiac cells. Reactive oxygen species (ROS)2 serve as both signaling molecules and destructive agents, requiring cells to finely regulate their levels. Antioxidant enzymes catalyze ROS conversion directly via an active-site metal ion (e.g. superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1-4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.In cardiac myocytes, ROS are a byproduct of mitochondrial electron transport (5) and are also produced by extramitochondrial sources, including NADPH oxidase (1), uncoupled nitric oxide synthase (6), xanthine oxidase (7), and monoamine oxidase (8, 9). Both mitochondrial and extramitochondrial sources have been implicated in cardiac disorders including heart failure, myocardial ischemia, and arrhythmias. The dynamics and steady-state levels of ROS in local intracellular domains are determined by the rates of free radical generation and scavenging. Failure to scavenge free radicals via antioxidant fluxes can trigger a vicious cycle of dysfunction, leading to death (10). Recent studies have demonstrated that antioxidant enzymes targeted to the mitochondria, but not the cytoplasm, protect agai...

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Section: Discussionmentioning

confidence: 99%

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Dey

Sidor

O’Rourke

2016

Journal of Biological Chemistry

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“…The activity of PRX3 might also be stimulated or supported by cytosolic CyP-A that binds to PRX3 apoptosis signaling pathway (Wonsey et al 2002;Chang et al 2004a). According to the previous studies, PRX3 oxidation is an early event in chemical-induced apoptosis of cancer cells (Cox et al 2008b;Brown et al 2008). As summarized in Table 2, there have been numerous reports indicating an active response of PRX3 to various proapoptotic stimuli (including anticancer chemicals) and the participation of PRX3 in cancer cell apoptosis.…”

Section: The Expression Of Prx3 and Its Involvement In Apoptosis Of Cmentioning

confidence: 97%

The functional role of peroxiredoxin 3 in reactive oxygen species, apoptosis, and chemoresistance of cancer cells

2015

J Cancer Res Clin Oncol

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“…In terms of other recognized influences of the Prx redox state on cell signaling, it is clear from work by Hampton and coworkers that Prx3, the most highly expressed Prx in mitochondria, plays an important role in modulating apoptosis (4). One idea that is gaining momentum is that Prx, by virtue of its rapid reaction with peroxides, may itself be a major redox sensor that transmits its oxidation signal not only to the Trx pool, but also to other target proteins (Fig.…”

Section: Mechanisms For Thiol Peroxidase Redox Switches In Higher Orgmentioning

confidence: 99%

Cysteine-Based Redox Switches in Enzymes

Klomsiri

Karplus²,

Poole³

2011

Antioxidants & Redox Signaling

328

268

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The enzymes involved in metabolism and signaling are regulated by posttranslational modifications that influence their catalytic activity, rates of turnover, and targeting to subcellular locations. Most prominent among these has been phosphorylation=dephosphorylation, but now a distinct class of modification coming to the fore is a set of versatile redox modifications of key cysteine residues. Here we review the chemical, structural, and regulatory aspects of such redox regulation of enzymes and discuss examples of how these regulatory modifications often work in concert with phosphorylation=dephosphorylation events, making redox dependence an integral part of many cell signaling processes. Included are the emerging roles played by peroxiredoxins, a family of cysteine-based peroxidases that now appear to be major players in both antioxidant defense and cell signaling.

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Mitochondrial peroxiredoxin 3 is rapidly oxidized in cells treated with isothiocyanates

Cited by 59 publications

References 40 publications

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

The functional role of peroxiredoxin 3 in reactive oxygen species, apoptosis, and chemoresistance of cancer cells

Cysteine-Based Redox Switches in Enzymes

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