The Experts below are selected from a list of 26082 Experts worldwide ranked by ideXlab platform
Dean P. Jones - One of the best experts on this subject based on the ideXlab platform.
-
hepatic oxidative stress in fructose induced fatty liver is not caused by sulfur amino acid insufficiency
Nutrients, 2011Co-Authors: Sachin Kunde, James R Roede, Miriam B Vos, Michael Orr, Youngja Park, Thomas R Ziegler, Dean P. JonesAbstract:Fructose-sweetened liquid consumption is associated with fatty liver and oxidative stress. In rodent models of fructose-mediated fatty liver, protein consumption is decreased. Additionally, decreased sulfur amino acid intake is known to cause oxidative stress. Studies were designed to test whether oxidative stress in fructose-sweetened liquid-induced fatty liver is caused by decreased ad libitum solid food intake with associated inadequate sulfur amino acid intake. C57BL6 mice were grouped as: control (ad libitum water), fructose (ad libitum 30% fructose-sweetened liquid), glucose (ad libitum 30% glucose-sweetened water) and pair-fed (ad libitum water and sulfur amino acid intake same as the fructose group). Hepatic and plasma thiol-disulfide antioxidant status were analyzed after five weeks. Fructose- and glucose-fed mice developed fatty liver. The mitochondrial antioxidant protein, Thioredoxin-2, displayed decreased abundance in the liver of fructose and glucose-fed mice compared to controls. Glutathione/glutathione disulfide redox potential (EhGSSG) and abundance of the cytoplasmic antioxidant protein, peroxiredoxin-2, were similar among groups. We conclude that both fructose and glucose-sweetened liquid consumption results in fatty liver and upregulated Thioredoxin-2 expression, consistent with mitochondrial oxidative stress; however, inadequate sulfur amino acid intake was not the cause of this oxidative stress.
-
maneb and paraquat mediated neurotoxicity involvement of peroxiredoxin Thioredoxin system
Toxicological Sciences, 2011Co-Authors: James R Roede, Jason M Hansen, Dean P. JonesAbstract:Epidemiological and in vivo studies have demonstrated that exposure to the pesticides paraquat (PQ) and maneb (MB) increase the risk of developing Parkinson’s disease (PD) and cause dopaminergic cell loss, respectively. PQ is a well-recognized cause of oxidative toxicity; therefore, the purpose of this study was to determine if MB potentiates oxidative stress caused by PQ, thus providing a mechanism for enhanced neurotoxicity by the combination. The results show that PQ alone at a moderately toxic dose (20–30% cell death in 24 h) caused increased reactive oxygen species (ROS) generation, oxidation of mitochondrial Thioredoxin-2 and peroxiredoxin-3, lesser oxidation of cytoplasmic Thioredoxin-1 and peroxiredoxin-1, and no oxidation of cellular GSH/GSSG. In contrast, MB alone at a similar toxic dose resulted in no ROS generation, no oxidation of Thioredoxin and peroxiredoxin, and an increase in cellular GSH after 24 h. Together, MB increased GSH and inhibited ROS production and Thioredoxin/peroxiredoxin oxidation observed with PQ alone, yet resulted in more extensive (> 50%) cell death. MB treatment resulted in increased abundance of nuclear Nrf2 and mRNA for phase II enzymes under the control of Nrf2, indicating activation of cell protective responses. The results show that MB potentiation of PQ neurotoxicity does not occur by enhancing oxidative stress and suggests that increased toxicity occurs by a combination of divergent mechanisms, perhaps involving alkylation by MB and oxidation by PQ.
-
a key role for mitochondria in endothelial signaling by plasma cysteine cystine redox potential
Free Radical Biology and Medicine, 2010Co-Authors: Heonyong Park, Michael Orr, Michael Koval, Matthew S Reed, Yongliang Liang, Debra Smith, Jan Pohl, Dean P. JonesAbstract:The redox potential of the plasma cysteine/cystine couple (EhCySS) is oxidized in association with risk factors for cardiovascular disease (CVD), including age, smoking, type 2 diabetes, obesity, and alcohol abuse. Previous in vitro findings support a cause–effect relationship for extracellular EhCySS in cell signaling pathways associated with CVD, including those controlling monocyte adhesion to endothelial cells. In this study, we provide evidence that mitochondria are a major source of reactive oxygen species (ROS) in the signaling response to a more oxidized extracellular EhCySS. This increase in ROS was blocked by overexpression of mitochondrial Thioredoxin-2 (Trx2) in endothelial cells from Trx2-transgenic mice, suggesting that mitochondrial thiol antioxidant status plays a key role in this redox signaling mechanism. Mass spectrometry-based redox proteomics showed that several classes of plasma membrane and cytoskeletal proteins involved in inflammation responded to this redox switch, including vascular cell adhesion molecule, integrins, actin, and several Ras family GTPases. Together, the data show that the proinflammatory effects of oxidized plasma EhCySS are due to a mitochondrial signaling pathway that is mediated through redox control of downstream effector proteins.
-
attenuation of angiotensin ii induced vascular dysfunction and hypertension by overexpression of Thioredoxin 2
Hypertension, 2009Co-Authors: Julian D Widder, Dean P. Jones, Jason M Hansen, Daniela Fraccarollo, Paolo Galuppo, Georg Ertl, Johann BauersachsAbstract:Reactive oxygen species increase in the cardiovascular system during hypertension and in response to angiotensin II. Because mitochondria contribute to reactive oxygen species generation, we sought to investigate the role of Thioredoxin 2, a mitochondria-specific antioxidant enzyme. Mice were created with overexpression of human Thioredoxin 2 (Tg(hTrx2) mice) and backcrossed to C57BL/6J mice for > or =6 generations. Twelve-week-old male Tg(hTrx2) or littermate wild-type mice were made hypertensive by infusion of angiotensin II (400 ng/kg per minute) for 14 days using osmotic minipumps. Systolic arterial blood pressure was not different between Tg(hTrx2) and wild-type animals under baseline conditions (101+/-1 respective 102+/-1 mm Hg). The angiotensin II-induced hypertension in wild-type mice (145+/-2 mm Hg) was significantly attenuated in Tg(hTrx2) mice (124+/-1 mm Hg; P<0.001). Aortic endothelium-dependent relaxation was significantly reduced in wild-type mice after angiotensin II infusion but nearly unchanged in transgenic mice. Elevated vascular superoxide and hydrogen peroxide levels, as well as expression of NADPH oxidase subunits in response to angiotensin II infusion, were significantly attenuated in Tg(hTrx2) mice. Mitochondrial superoxide anion levels were augmented after angiotensin II infusion in wild-type mice, and this was blunted in Tg(hTrx2) mice. Angiotensin II infusion significantly increased myocardial superoxide formation, heart weight, and cardiomyocyte size in wild-type but not in Tg(hTrx2) mice. These data indicate a major role for mitochondrial Thioredoxin 2 in the development of cardiovascular alterations and hypertension during chronic angiotensin II infusion. Thioredoxin 2 may represent an important therapeutic target for the prevention and treatment of hypertension and oxidative stress.
-
redox compartmentalization in eukaryotic cells
Biochimica et Biophysica Acta, 2008Co-Authors: Dean P. JonesAbstract:Diverse functions of eukaryotic cells are optimized by organization of compatible chemistries into distinct compartments defined by the structures of lipid-containing membranes, multiprotein complexes and oligomeric structures of saccharides and nucleic acids. This structural and chemical organization is coordinated, in part, through cysteine residues of proteins which undergo reversible oxidation-reduction and serve as chemical/structural transducing elements. The central thiol/disulfide redox couples, Thioredoxin-1, Thioredoxin-2, GSH/GSSG and cysteine/cystine (Cys/CySS), are not in equilibrium with each other and are maintained at distinct, non-equilibrium potentials in mitochondria, nuclei, the secretory pathway and the extracellular space. Mitochondria contain the most reducing compartment, have the highest rates of electron transfer and are highly sensitive to oxidation. Nuclei also have more reduced redox potentials but are relatively resistant to oxidation. The secretory pathway contains oxidative systems which introduce disulfides into proteins for export. The cytoplasm contains few metabolic oxidases and this maintains an environment for redox signaling dependent upon NADPH oxidases and NO synthases. Extracellular compartments are maintained at stable oxidizing potentials. Controlled changes in cytoplasmic GSH/GSSG redox potential are associated with functional state, varying with proliferation, differentiation and apoptosis. Variation in extracellular Cys/CySS redox potential is also associated with proliferation, cell adhesion and apoptosis. Thus, cellular redox biology is inseparable from redox compartmentalization. Further elucidation of the redox control networks within compartments will improve the mechanistic understanding of cell functions and their disruption in disease.
Maria Pia Rigobello - One of the best experts on this subject based on the ideXlab platform.
-
significance of the mitochondrial Thioredoxin reductase in cancer cells an update on role targets and inhibitors
Free Radical Biology and Medicine, 2018Co-Authors: Valeria Scalcon, Alberto Bindoli, Maria Pia RigobelloAbstract:Abstract Thioredoxin reductase 2 (TrxR2) is a key component of the mitochondrial Thioredoxin system able to transfer electrons to peroxiredoxin 3 (Prx3) in a reaction mediated by Thioredoxin 2 (Trx2). In this way, both the level of hydrogen peroxide and thiol redox state are modulated. TrxR2 is often overexpressed in cancer cells conferring apoptosis resistance. Due to their exposed flexible arm containing selenocysteine, both cytosolic and mitochondrial TrxRs are inhibited by a large number of molecules. The various classes of inhibitors are listed and the molecules acting specifically on TrxR2 are extensively described. Particular emphasis is given to gold(I/III) complexes with phosphine, carbene or other ligands and to tamoxifen-like metallocifens. Also chemically unrelated organic molecules, including natural compounds and their derivatives, are taken into account. An important feature of many TrxR2 inhibitors is provided by their nature of delocalized lipophilic cations that allows their accumulation in mitochondria exploiting the organelle membrane potential. The consequences of TrxR2 inhibition are presented focusing especially on the impact on mitochondrial pathophysiology. Inhibition of TrxR2, by hindering the activity of Trx2 and Prx3, increases the mitochondrial concentration of reactive oxygen species and shifts the thiol redox state toward a more oxidized condition. This is reflected by alterations of specific targets involved in the release of pro-apoptotic factors such as cyclophilin D which acts as a regulator of the mitochondrial permeability transition pore. Therefore, the selective inhibition of TrxR2 could be utilized to induce cancer cell apoptosis.
-
Tamoxifen-like metallocifens target the Thioredoxin system determining mitochondrial impairment leading to apoptosis in Jurkat cells
Metallomics, 2017Co-Authors: Valeria Scalcon, Alessandra Folda, Alberto Bindoli, Michèle Salmain, Siden Top, Pascal Pigeon, Hui Zhi Shirley Lee, Gérard Jaouen, Anne Vessieres, Maria Pia RigobelloAbstract:Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, and Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. In contrast, the Thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the Thioredoxin system and evaluated the input of the metallocene unit in comparison with structurally related organic tamoxifens. In vitro, all three TLMs became strong inhibitors of the cytosolic (TrxR1) and mitochondrial (TrxR2) isoforms of Thioredoxin reductase after enzymatic oxidation with HRP/H2O2 while none of the organic analogues was effective. In Jurkat cells, TLMs inhibited mainly TrxR2, resulting in the accumulation of oxidized Thioredoxin 2 and cell redox imbalance. Overproduction of ROS resulted in a strong decrease in the mitochondrial membrane potential, translocation of cytochrome c to the cytosol and activation of caspase 3, thus leading to apoptosis. None of these events occurred with organic tamoxifens. The mitochondrial fraction of cells exposed to TLMs contained a high amount of the corresponding metal, as quantified by ICP-OES. The lipophilic and cationic character associated with the singular redox properties of the TLMs could explain why they alter the mitochondrial function. These results provide new insights into the mechanism of action of tamoxifen-like metallocifens, underlying their prodrug behaviour and the pivotal role played by the metallocenic entity in their cytotoxic activity associated with the induction of apoptosis.
-
Mitochondrial Thioredoxin System as a Modulator of Cyclophilin D Redox State
Scientific reports, 2016Co-Authors: Alessandra Folda, Anna Citta, Valeria Scalcon, Tito Calì, Francesco Zonta, Guido Scutari, Alberto Bindoli, Maria Pia RigobelloAbstract:The mitochondrial Thioredoxin system (NADPH, Thioredoxin reductase, Thioredoxin) is a major redox regulator. Here we have investigated the redox correlation between this system and the mitochondrial enzyme cyclophilin D. The peptidyl prolyl cis-trans isomerase activity of cyclophilin D was stimulated by the Thioredoxin system, while it was decreased by cyclosporin A and the Thioredoxin reductase inhibitor auranofin. The redox state of cyclophilin D, Thioredoxin 1 and 2 and peroxiredoxin 3 was measured in isolated rat heart mitochondria and in tumor cell lines (CEM-R and HeLa) by redox Western blot analysis upon inhibition of Thioredoxin reductase with auranofin, arsenic trioxide, 1-chloro-2,4-dinitrobenzene or after treatment with hydrogen peroxide. A concomitant oxidation of Thioredoxin, peroxiredoxin and cyclophilin D was observed, suggesting a redox communication between the Thioredoxin system and cyclophilin. This correlation was further confirmed by i) co-immunoprecipitation assay of cyclophilin D with Thioredoxin 2 and peroxiredoxin 3, ii) molecular modeling and iii) depleting Thioredoxin reductase by siRNA. We conclude that the mitochondrial Thioredoxin system controls the redox state of cyclophilin D which, in turn, may act as a regulator of several processes including ROS production and pro-apoptotic factors release.
-
gold i carbene complexes causing Thioredoxin 1 and Thioredoxin 2 oxidation as potential anticancer agents
Journal of Medicinal Chemistry, 2012Co-Authors: Esther Schuh, Alessandra Folda, Anna Citta, Alberto Bindoli, Maria Pia Rigobello, Carolin Pfluger, Angela Casini, Fabian MohrAbstract:Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as Thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of Thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.
Nazareno Paolocci - One of the best experts on this subject based on the ideXlab platform.
-
Thioredoxin reductase 2 is essential for keeping low levels of h 2 o 2 emission from isolated heart mitochondria
Journal of Biological Chemistry, 2011Co-Authors: Brian A Stanley, Walter H Watson, Sa Shi, Vidhya Sivakumaran, Iain Mcdonald, David Lloyd, Miguel A Aon, Nazareno PaolocciAbstract:Respiring mitochondria produce H2O2 continuously. When production exceeds scavenging, H2O2 emission occurs, endangering cell functions. The mitochondrial peroxidase peroxiredoxin-3 reduces H2O2 to water using reducing equivalents from NADPH supplied by Thioredoxin-2 (Trx2) and, ultimately, Thioredoxin reductase-2 (TrxR2). Here, the contribution of this mitochondrial Thioredoxin system to the control of H2O2 emission was studied in isolated mitochondria and cardiomyocytes from mouse or guinea pig heart. Energization of mitochondria by the addition of glutamate/malate resulted in a 10-fold decrease in the ratio of oxidized to reduced Trx2. This shift in redox state was accompanied by an increase in NAD(P)H and was dependent on TrxR2 activity. Inhibition of TrxR2 in isolated mitochondria by auranofin resulted in increased H2O2 emission, an effect that was seen under both forward and reverse electron transport. This effect was independent of changes in NAD(P)H or membrane potential. The effects of auranofin were reproduced in cardiomyocytes; superoxide and H2O2 levels increased, but similarly, there was no effect on NAD(P)H or membrane potential. These data show that energization of mitochondria increases the antioxidant potential of the TrxR2/Trx2 system and that inhibition of TrxR2 results in increased H2O2 emission through a mechanism that is independent of changes in other redox couples.
-
Thioredoxin reductase 2 is essential for keeping low levels of h2o2 emission from isolated heart mitochondria
Journal of Biological Chemistry, 2011Co-Authors: Brian A Stanley, Walter H Watson, Sa Shi, Vidhya Sivakumaran, Iain Mcdonald, David Lloyd, Miguel A Aon, Nazareno PaolocciAbstract:Respiring mitochondria produce H2O2 continuously. When production exceeds scavenging, H2O2 emission occurs, endangering cell functions. The mitochondrial peroxidase peroxiredoxin-3 reduces H2O2 to water using reducing equivalents from NADPH supplied by Thioredoxin-2 (Trx2) and, ultimately, Thioredoxin reductase-2 (TrxR2). Here, the contribution of this mitochondrial Thioredoxin system to the control of H2O2 emission was studied in isolated mitochondria and cardiomyocytes from mouse or guinea pig heart. Energization of mitochondria by the addition of glutamate/malate resulted in a 10-fold decrease in the ratio of oxidized to reduced Trx2. This shift in redox state was accompanied by an increase in NAD(P)H and was dependent on TrxR2 activity. Inhibition of TrxR2 in isolated mitochondria by auranofin resulted in increased H2O2 emission, an effect that was seen under both forward and reverse electron transport. This effect was independent of changes in NAD(P)H or membrane potential. The effects of auranofin were reproduced in cardiomyocytes; superoxide and H2O2 levels increased, but similarly, there was no effect on NAD(P)H or membrane potential. These data show that energization of mitochondria increases the antioxidant potential of the TrxR2/Trx2 system and that inhibition of TrxR2 results in increased H2O2 emission through a mechanism that is independent of changes in other redox couples.
Sa Shi - One of the best experts on this subject based on the ideXlab platform.
-
Thioredoxin 2 offers protection against mitochondrial oxidative stress in h9c2 cells and against myocardial hypertrophy induced by hyperglycemia
International Journal of Molecular Sciences, 2017Co-Authors: Xiuxiang Gao, Erkio Sugano, Hiroshi Tomita, Liming Yang, Sa ShiAbstract:Mitochondrial oxidative stress is thought to be a key contributor towards the development of diabetic cardiomyopathy. Thioredoxin 2 (Trx2) is a mitochondrial antioxidant that, along with Trx reductase 2 (TrxR2) and peroxiredoxin 3 (Prx3), scavenges H₂O₂ and offers protection against oxidative stress. Our previous study showed that TrxR inhibitors resulted in Trx2 oxidation and increased ROS emission from mitochondria. In the present study, we observed that TrxR inhibition also impaired the contractile function of isolated heart. Our studies showed a decrease in the expression of Trx2 in the high glucose-treated H9c2 cardiac cells and myocardium of streptozotocin (STZ)-induced diabetic rats. Overexpression of Trx2 could significantly diminish high glucose-induced mitochondrial oxidative damage and improved ATP production in cultured H9c2 cells. Notably, Trx2 overexpression could suppress high glucose-induced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. Our studies suggest that high glucose-induced mitochondrial oxidative damage can be prevented by elevating Trx2 levels, thereby providing extensive protection to the diabetic heart.
-
Thioredoxin reductase 2 is essential for keeping low levels of h 2 o 2 emission from isolated heart mitochondria
Journal of Biological Chemistry, 2011Co-Authors: Brian A Stanley, Walter H Watson, Sa Shi, Vidhya Sivakumaran, Iain Mcdonald, David Lloyd, Miguel A Aon, Nazareno PaolocciAbstract:Respiring mitochondria produce H2O2 continuously. When production exceeds scavenging, H2O2 emission occurs, endangering cell functions. The mitochondrial peroxidase peroxiredoxin-3 reduces H2O2 to water using reducing equivalents from NADPH supplied by Thioredoxin-2 (Trx2) and, ultimately, Thioredoxin reductase-2 (TrxR2). Here, the contribution of this mitochondrial Thioredoxin system to the control of H2O2 emission was studied in isolated mitochondria and cardiomyocytes from mouse or guinea pig heart. Energization of mitochondria by the addition of glutamate/malate resulted in a 10-fold decrease in the ratio of oxidized to reduced Trx2. This shift in redox state was accompanied by an increase in NAD(P)H and was dependent on TrxR2 activity. Inhibition of TrxR2 in isolated mitochondria by auranofin resulted in increased H2O2 emission, an effect that was seen under both forward and reverse electron transport. This effect was independent of changes in NAD(P)H or membrane potential. The effects of auranofin were reproduced in cardiomyocytes; superoxide and H2O2 levels increased, but similarly, there was no effect on NAD(P)H or membrane potential. These data show that energization of mitochondria increases the antioxidant potential of the TrxR2/Trx2 system and that inhibition of TrxR2 results in increased H2O2 emission through a mechanism that is independent of changes in other redox couples.
-
Thioredoxin reductase 2 is essential for keeping low levels of h2o2 emission from isolated heart mitochondria
Journal of Biological Chemistry, 2011Co-Authors: Brian A Stanley, Walter H Watson, Sa Shi, Vidhya Sivakumaran, Iain Mcdonald, David Lloyd, Miguel A Aon, Nazareno PaolocciAbstract:Respiring mitochondria produce H2O2 continuously. When production exceeds scavenging, H2O2 emission occurs, endangering cell functions. The mitochondrial peroxidase peroxiredoxin-3 reduces H2O2 to water using reducing equivalents from NADPH supplied by Thioredoxin-2 (Trx2) and, ultimately, Thioredoxin reductase-2 (TrxR2). Here, the contribution of this mitochondrial Thioredoxin system to the control of H2O2 emission was studied in isolated mitochondria and cardiomyocytes from mouse or guinea pig heart. Energization of mitochondria by the addition of glutamate/malate resulted in a 10-fold decrease in the ratio of oxidized to reduced Trx2. This shift in redox state was accompanied by an increase in NAD(P)H and was dependent on TrxR2 activity. Inhibition of TrxR2 in isolated mitochondria by auranofin resulted in increased H2O2 emission, an effect that was seen under both forward and reverse electron transport. This effect was independent of changes in NAD(P)H or membrane potential. The effects of auranofin were reproduced in cardiomyocytes; superoxide and H2O2 levels increased, but similarly, there was no effect on NAD(P)H or membrane potential. These data show that energization of mitochondria increases the antioxidant potential of the TrxR2/Trx2 system and that inhibition of TrxR2 results in increased H2O2 emission through a mechanism that is independent of changes in other redox couples.
Garth Powis - One of the best experts on this subject based on the ideXlab platform.
-
increased expression of mitochondrial peroxiredoxin 3 Thioredoxin peroxidase 2 protects cancer cells against hypoxia and drug induced hydrogen peroxide dependent apoptosis
Molecular Cancer Research, 2003Co-Authors: Larisa Nonn, Margareta Berggren, Garth PowisAbstract:Peroxiredoxin-3 (Prdx3) is a mitochondrial member of the antioxidant family of Thioredoxin peroxidases that uses mitochondrial Thioredoxin-2 (Trx2) as a source of reducing equivalents to scavenge hydrogen peroxide (H2O2). Low levels of H2O2 produced by the mitochondria regulate physiological processes, including cell proliferation, while high levels of H2O2 are toxic to the cell and cause apoptosis. WEHI7.2 thymoma cells with stable overexpression of Prdx3 displayed decreased levels of cellular H2O2 and decreased cell proliferation without a change in basal levels of apoptosis. Prdx3-transfected cells showed a marked resistance to hypoxia-induced H2O2 formation and apoptosis. Prdx3 overexpression also protected the cells against apoptosis caused by H2O2, t-butylhydroperoxide, and the anticancer drug imexon, but not by dexamethasone. Thus, mitochondrial Prdx3 is an important cellular antioxidant that regulates physiological levels of H2O2, leading to decreased cell growth while protecting cells from the apoptosisinducing effects of high levels of H2O2.
-
the absence of mitochondrial Thioredoxin 2 causes massive apoptosis exencephaly and early embryonic lethality in homozygous mice
Molecular and Cellular Biology, 2003Co-Authors: Larisa Nonn, Ryan R Williams, Robert P Erickson, Garth PowisAbstract:Thioredoxin 2 (Trx-2) is a small redox protein containing the Thioredoxin active site Trp-Cys-Gly-Pro-Cys that is localized to the mitochondria by a mitochondrial leader sequence and encoded by a nuclear gene (Trx-2). Trx-2 plays an important role in cell viability and the regulation of apoptosis in vitro. To investigate the role of Trx-2 in mouse development, we studied the phenotype of mice that have the Trx-2 gene silenced by mutational insertion. Homozygous mutant embryos do not survive to birth and die after implantation at Theiler stage 15/16. The homozygous mutant embryos display an open anterior neural tube and show massively increased apoptosis at 10.5 days postcoitus and are not present by 12.5 days postcoitus. The timing of the embryonic lethality coincides with the maturation of the mitochondria, since they begin oxidative phosphorylation during this stage of embryogenesis. In addition, embryonic fibroblasts cultured from homozygous Trx-2-null embryos were not viable. Heterozygous mice are fertile and have no discernible phenotype visible by external observation, despite having decreased Trx-2 mRNA and protein. These results show that the mitochondrial redox protein Trx-2 is required for normal development of the mouse embryo and for actively respiring cells.
-
Increased expression of mitochondrial peroxiredoxin-3 (Thioredoxin peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxide-dependent apoptosis.
Molecular cancer research : MCR, 2003Co-Authors: Larisa Nonn, Margareta Berggren, Garth PowisAbstract:Peroxiredoxin-3 (Prdx3) is a mitochondrial member of the antioxidant family of Thioredoxin peroxidases that uses mitochondrial Thioredoxin-2 (Trx2) as a source of reducing equivalents to scavenge hydrogen peroxide (H2O2). Low levels of H2O2 produced by the mitochondria regulate physiological processes, including cell proliferation, while high levels of H2O2 are toxic to the cell and cause apoptosis. WEHI7.2 thymoma cells with stable overexpression of Prdx3 displayed decreased levels of cellular H2O2 and decreased cell proliferation without a change in basal levels of apoptosis. Prdx3-transfected cells showed a marked resistance to hypoxia-induced H2O2 formation and apoptosis. Prdx3 overexpression also protected the cells against apoptosis caused by H2O2, t-butylhydroperoxide, and the anticancer drug imexon, but not by dexamethasone. Thus, mitochondrial Prdx3 is an important cellular antioxidant that regulates physiological levels of H2O2, leading to decreased cell growth while protecting cells from the apoptosisinducing effects of high levels of H2O2.