Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling

Cox, Andrew G.; Winterbourn, Christine C.; Hampton, Mark B.

doi:10.1042/bj20091541

Cited by 432 publications

(357 citation statements)

References 194 publications

(249 reference statements)

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“…The kinetic contribution to scavenging for each component depends on the concentration of the electron donors, redox potential of the couple, enzyme concentration, and rate of the reaction with hydrogen peroxide. Taking these factors into account, Cox et al (23) proposed that the relative abundance and kinetic properties of PRX3 favor it as the predominant mitochondrial scavenger of H 2 O 2 compared with other peroxidases. On the other hand, GSH is present in millimolar amounts within the cell (24) and represents the largest-capacity redox reserve (25).…”

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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“…Some evidence obtained from animal studies supports this idea. Mice overexpressing glutathione peroxidase, Gpx1, developed insulin resistance associated with hyperinsulinemia, hyperglycemia, obesity and a 70% reduction in insulinstimulated phosphorylation of insulin receptors, compared to wild type control mice [98]. On the contrary, mice lacking Gpx1 were protected from high-fat diet-induced insulin resistance, while administration of NAC rendered them more insulin-resistant and increased fasting glucose levels in the blood [99].…”

Section: Relationships Between Insulin-induced H 2 O 2 and Antioxidanmentioning

confidence: 99%

H2O2 Signalling Pathway: A Possible Bridge between Insulin Receptor and Mitochondria

Помыткин¹

2012

Current Neuropharmacology

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This review is focused on the mechanistic aspects of the insulin-induced H 2 O 2 signalling pathway in neurons and the molecules affecting it, which act as risk factors for developing central insulin resistance. Insulin-induced H 2 O 2 promotes insulin receptor activation and the mitochondria act as the insulin-sensitive H 2 O 2 source, providing a direct molecular link between mitochondrial dysfunction and irregular insulin receptor activation. In this view, the accumulation of dysfunctional mitochondria during chronological ageing and Alzheimer's disease (AD) is a risk factor that may contribute to the development of dysfunctional cerebral insulin receptor signalling and insulin resistance. Due to the high significance of insulin-induced H 2 O 2 for insulin receptor activation, oxidative stress-induced upregulation of antioxidant enzymes, e.g., in AD brains, may represent another risk factor contributing to the development of insulin resistance. As insulin-induced H 2 O 2 signalling requires fully functional mitochondria, pharmacological strategies based on activating mitochondria biogenesis in the brain are central to the treatment of diseases associated with dysfunctional insulin receptor signalling in this organ.

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“…TrxRs occurs as homodimers and play a critical role in the NADPH-dependent TrxR-Trx system, which reduces peroxides both directly and indirectly via the reductive activities of Trx (which reduces disulfides) and peroxiredoxins [which remove H 2 O 2 and some other oxidants (43,44)]. …”

Section: Role Of Selenium-containing Amino Acids As Catalytically Actmentioning

confidence: 99%

Selenium‐containing amino acids as direct and indirect antioxidants

2012

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SummarySelenium is a trace element essential for normal physiological processes. Organic selenium-containing amino acids, such as selenocysteine (Sec) / selenocystine and selenomethionine (SeMet, the major dietary form), can provide antioxidant benefits by acting both as direct antioxidants as well as a source of selenium for synthesis of selenium-dependent antioxidant and repair proteins (e.g., glutathione peroxidases, thioredoxin reductases, methionine sulfoxide reductases). The direct antioxidant actions of these amino acids arise from the nucleophilic properties of the ionized selenol (RSe 2 , which predominates over the neutral form at physiological pH values) and the ease of oxidation of Sec and SeMet. This results in higher rate constants for reaction with multiple oxidants, than for the corresponding thiols/thioethers. Furthermore, the resulting oxidation products are more readily and rapidly reversed by both enzyme and nonenzymatic reactions. The antioxidant effects of these seleno species can therefore be catalytic. Seleno amino acids may also chelate redox-active metal ions. The presence of Sec in the catalytic site of seleniumdependent antioxidant enzymes enhances the kinetic properties and broadens the catalytic activity of antioxidant enzymes against biological oxidants when compared with sulfur-containing species. However, while normal physiological selenium levels afford protection, when compared with deficiency, excessive selenium may induce damage and adverse effects, with this being manifest, for example, as an increased incidence of type 2 diabetes. Further studies examining the availability of redox-active selenium species and their mechanisms and kinetics of action are therefore of critical importance in the potential development of seleno species as a therapeutic strategy.2012 IUBMB IUBMB Life, 64(11): 863-871, 2012

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Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling

Cited by 432 publications

References 194 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

H2O2 Signalling Pathway: A Possible Bridge between Insulin Receptor and Mitochondria

Selenium‐containing amino acids as direct and indirect antioxidants

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