Maintaining redox homeostasis is crucial for normal cellular functions. Electron leak by the cytochrome P450 enzymes renders steroidogenic tissues acutely vulnerable to redox imbalance and oxidative stress is implicated in several potentially lethal adrenal disorders. This thesis aims to further delineate the role of oxidative stress in triple A syndrome and familial glucocorticoid deficiency (FGD). Triple A syndrome incorporates adrenal failure and progressive neurodegenerative disease. The AAAS gene product is the nuclear pore complex protein ALADIN, of unknown function. Patient dermal fibroblasts are sensitive to oxidative stress, with failure of nuclear import of DNA repair proteins and ferritin heavy chain protein. To provide an adrenal and neuronal-specific disease model, I established AAAS-knockdown in H295R human adrenocortical tumour cells and SH-SY5Y human neuroblastoma cells. This had effects on cell viability, exacerbated by hydrogen peroxide treatment. Redox homeostasis was impaired in AAAS-knockdown H295R cells, with depletion of key components of the steroidogenic pathway and a significant reduction in cortisol production, with partial reversal following treatment with N-acetylcysteine. Mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase (NNT), causing FGD, have recently highlighted the importance of redox regulation in steroidogenesis. I investigated seven individuals from a consanguineous Kashmiri kindred, mutation negative for known causes of FGD. A stop gain mutation, p.Y447* in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 segregated with the disease trait; with complete absence of the 56 kDa TXNRD2 protein in patients homozygous for the mutation. TXNRD2-knockdown led to impaired redox homeostasis in H295R cells. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.

Iron plays a potential role in oxidative stress-mediated injuries and pathologies e.g. rheumatoid arthritis (RA). Four decades ago it was suggested that iron may have a crucial role in the progression of inflammation in RA. Indeed, free radicals generated by iron can cause damage to lipids, proteins, carbohydrates, and DNA. It is this destructive process that is believed to occur in rheumatoid joints. However, none had differentiated between the role of iron in both acute and chronic phases of the disease and the origin of this 'labile' iron. Since RA cells are chronically exposed to oxidative stress, we have therefore chosen Jurkat cells to be our cell model. We used the parental (J16) cell line was used to mimic the acute phase of oxidative stress and the H2O2-resistant (HJ16) cells to mimic the chronic phase. By using hydrogen peroxide (H2O2) as the oxidising agent, we aim to study the role of iron in acute and chronic phase of oxidative stress and to know its origin. In the present study, we found that both antioxidants and H2O2-induced labile iron are modulated when cells are chronically exposed to H2O2. HJ16 cells contain higher total intracellular glutathione levels and glutathione peroxidase activity than J16 cells while the superoxide dismutase and catalase activity are similar. Haem oxygenase-1 (HO-1) was not detectable nor was it induced in these cell lines; HO-2 on the other hand was expressed but not induced. Although they had the same ‘basal’ LIP and L-Ft levels, J16 cells contain more than 7-fold higher H-Ft levels than in HJ16 cells. It was also found that H2O2-induced labile iron is directly correlated with necrotic cell death. These results are consistent with the conclusion that both antioxidant defence mechanism and labile iron status are modulated in cells chronically exposed to H2O2. We have also shown that the ‘basal’ and ‘H2O2-induced’ NFκB activation was higher in the HJ16 cells. We have also provided a link between labile iron release, lysosomal membrane damage and the ensuing necrotic cell death following H2O2 treatment.

One third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes TB. During an infection, bacteria often survive host immune system attacks, which include oxidative stress conditions for bacteria growing inside macrophages. This makes treatment difficult and time-consuming. We hypothesize bacteria can adapt to environmental conditions by changing their mRNA maturation and degradation profiles. Using a model system, Mycobacteruim smegmatis, we focus on how mRNA expression is affected by oxidative stress. After construction and sequencing of RNA expression libraries, preliminary analysis showed that after three hours of H2O2 exposure most upregulated genes were related to DNA repair, while downregulated genes included transport proteins. After six hours of exposure, upregulated genes were similar to three hours and downregulated genes included tRNAs. 5' end mapping libraries were also constructed to access differential cleavage site abundance under oxidative stress conditions. We also investigated the roles RNase J may have in stress response and mRNA processing in Mycobacteria. RNase J and RNase E are thought to be the major RNases in bacteria. While most bacteria only have one of them, mycobacteria encode both in their genome, with RNase J being non-essential. We constructed a set of 4 strains (WT, RNase J overexpression, RNase J deletion, and complemented RNase J deletion) and tested their drug resistance and stress tolerance. Results suggests that RNase J deletion and overexpression alter drug sensitivity. Stress tolerance assays showed that WT is more tolerant to oxidative stress, followed by RNase J deletion strain and overexpression and complemented RNase J deletion strains, with the last two showing no growth when cultured with H2O2. Analysis of the expression profile of these strains was performed to help understand if gene expression differences are responsible for the phenotypes observed. For the complemented RNase J deletion, one operon had almost all its genes upregulated. This operon encodes a hydrogenase (Hyd3), suggesting that redox balance in the strain is perturbed.

A ovariectomia bilateral em ratas é um dos modelos experimentais utilizados para se analisar a menopausa e as possíveis estratégias para amenizar os efeitos deletérios desta condição. A suplementação da dieta com antioxidantes vem sendo utilizada para diminuir o risco de estresse oxidativo, que está aumentado na menopausa. Nesse estudo, foram analisados os efeitos do ácido lipoico (AL) e dos ômegas-3 (ácido docosahexaenóico (DHA) e ácido eicosapentaenóico (EPA)) no fígado, através da suplementação da dieta de ratas ovariectomizadas. O ácido lipoico foi escolhido em virtude da sua capacidade antioxidante, pela conhecida característica de ser cofator de enzimas chave no metabolismo celular e por inibir alguns mecanismos pró- inflamatórios. Essas características são importantes em virtude da disfunção mitocondrial e do aumento dos níveis de citocinas inflamatórias, que estão presentes após a menopausa. Os demais ácidos graxos poli-insaturados foram utilizados por possuírem alta capacidade antioxidante e estarem bem estabelecidos como protetores endoteliais. Além disso, também exercem efeitos anti-inflamatórios e são capazes de normalizar os níveis de lipídios na circulação sanguínea. Os resultados demonstram que o ácido lipoico é capaz de atuar no fígado e recuperar a atividade da enzima fumarase e a atividade das enzimas antioxidantes superóxido dismutase mitocondrial (MnSOD) e glutationa peroxidase (GPx), além de diminuir o dano oxidativo em proteínas e manter os níveis de malondialdeído (MDA) semelhantes ao grupo controle. No entanto, não exerceu influência na atividade da superóxido dismutase citosólica (CuZnSOD). A suplementação com DHA e EPA restaurou os níveis das duas classes de superóxidos dismutase, mas, não conseguiu restaurar a atividade da GPx e da fumarase. Os níveis de proteínas danificadas foram menores em todos os animais suplementados com ômega-3 em relação ao grupo controle e ao grupo ovariectomizado sem suplementação. Além disso, os suplementos também atuaram na redução dos níveis de nitritos e nitratos pois possuem propriedades anti-inflamatórias, sobretudo o ácido lipoico, que inibe a oxido nítrico sintase induzível (ONi) de macrófagos. Os níveis de vitamina C não apresentaram diferença entre os grupos SHAM, OVX, AL e DHA. Mas, o grupo EPA apresentou níveis de vitamina C inferiores aos dos grupos SHAM e OVX. Além disso, os níveis de vitamina E se mostraram inferiores nos grupos suplementados com os ácidos graxos poli-insaturados de cadeia longa. Neste trabalho, os antioxidantes assumiram um papel importante na diminuição do dano oxidativo e na recuperação da atividade de enzimas importantes na homeostase celular, alterações essas, causadas pela diminuição drástica dos níveis de estrogênio no modelo de menopausa. / The bilateral ovariectomy in rats is one of the experimental models used to analyze the menopause and possible strategies to mitigate the deleterious effects of this condition. Dietary supplementation with antioxidants has been used to decrease the risk of oxidative stress, which is increased in menopause. In this study, it was analyzed the effects of lipoic acid (LA) and the omega -3 (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) in the liver, through dietary supplementation of ovariectomized rats. The lipoic acid was chosen because of its antioxidant capacity, its known characteristic of being cofactor for key enzymes in cellular metabolism, and inhibition of some proinflammatory mechanisms. These characteristics are important because of mitochondrial dysfunction and increased levels of inflammatory cytokines, that are present after menopause. The other polyunsaturated fatty acids were used due to their high antioxidant capacity and well established endothelial protective role. Furthermore, they also exert anti-inflammatory effects and are able to normalize the lipid levels in the bloodstream. The results showed that lipoic acid is capable of acting in the liver and recover the activities of the fumarase enzyme and the antioxidant enzymes mitochondrial superoxide dismutase (MnSOD) and glutathione peroxidase (GPx), and reducing oxidative damage of proteins and maintaining the levels of malondialdehyde (MDA) similar to the control group. However, lipoic acid had no influence on the activity of cytosolic superoxide dismutase (CuZnSOD). Supplementation with DHA and EPA restored the levels of both classes of superoxide dismutase, but was unable to restore the activity of GPx and fumarase. The levels of damaged proteins were lower in all animals supplemented with omega -3 when compared to the sham and ovariectomized groups without supplementation. Also, the supplements were active in reducing levels of nitrites and nitrates, since they have anti -inflammatory properties, especially lipoic acid, which inhibits nitric oxide synthase inducible (iNOS) of macrophages. Vitamin C levels did not differ between the SHAM, LA, OVX and DHA groups. But the EPA group presented lower levels of vitamin C than those of SHAM and OVX groups. Nonetheless, levels of vitamin E was inferior in the groups supplemented with long chain polyunsaturated fatty acids. In this work, antioxidants played an important role in reducing oxidative damage and assists recovery of the activity of important enzymes in cellular homeostasis, changes caused by the drastic decrease in estrogen levels in menopausal model.

Introduction: Despite intense research efforts and improvements to mortality rates, breast cancer remains the leading cause of premature cancer death for women. Identifying women at highest risk is vitally important for screening decisions that may have a critical impact on diagnosis and prognosis. A family history of breast cancer is a well-established risk factor, but it can be unreliable. An easily measured and accurate biomarker of breast cancer risk would be a significant advancement to public health by allowing targeted screening of women who would benefit most. It may also reveal underlying molecular mechanism that could illuminate pathways to prevention. Incidence rates of breast cancer have remained unmoved owing to the lack of known modifiable risk factors. This may be due in part because most breast cancer research has focused on behaviors and exposures in, or recalled from, adulthood. The studies detailed in this dissertation seek to investigate the associations between oxidative stress and breast cancer risk in both adult women and adolescent girls with a family history of breast cancer. Methods: To determine the relationship between oxidative stress and breast cancer risk in adult women with a family history of breast cancer we measured and compared urinary levels of 8-OxodG and F2-Isoprostane in a prospective matched case control study nested within the New York Breast Cancer Family Registry. Cases (N=73) were individually matched with 2 controls on age, year of urine donation, menopausal status, and race. Conditional logistic regression methods were used to determine the odds of breast cancer from oxidative stress controlling for other risk factors for breast cancer and potential confounders. To better understand how oxidative stress levels change during puberty in girls and if such change is modified by a family history of breast cancer, we measured and compared levels of those same urinary biomarkers of oxidative stress in adolescent girls with and without a family history of breast cancer from the New York site of the Lessons in Epidemiology and Genetics of Adult Cancer from Youth cohort (LEGACY). Oxidative stress levels were measured both cross-sectionally at baseline and longitudinally every 6-months for up to 18-months. Linear regression was used for the cross-sectional analysis and repeated measures analysis using mixed models was employed for the longitudinal analysis. In both studies, biomarker levels were measured using well-established ELISA methods and adjusted for hydration status using specific gravity. Results: In the case control study of adult women we found that both 8-OxodG and F2-Isoprostane levels were significantly associated with a reduced risk of breast cancer after adjusting for BRCA1/2 mutation status, time between menarche and parity or menopause, and BMI (8-OxodG: β10-unit= -0.14, OR=0.87, p=0.03; F2-Isoprostane: β10-unit = -0.53, OR=0.59 , p=0.03). This inverse association was strongest among women under 50 and in women with a BMI below 25 for both biomarkers, and among women who reached menarche before age 14 for F2-Isoprostane. Overall, women in the highest tertile of either oxidative stress biomarker had approximately 50% reduced odds of breast cancer diagnosis. In our cross-sectional study of adolescent girls, we found that there was no significant difference in either oxidative stress biomarker in girls based on their family history of breast cancer. F2-Isoprostane levels were significantly associated with breast development measured by Tanner stage even after adjusting for age, age-specific BMI category and race (β=0.28, p=0.01). 8-OxodG levels were not significantly associated with age, BMI, race or Tanner stage at baseline but they were significantly associated with overweight/obese BMI but only among girls with a breast cancer family history (β=0.47, p=0.01). Change in 8-OxodG levels was significantly higher over the follow-up period in girls with a family history of breast cancer. This result remained significant after categorical measures of age, BMI, Tanner breast stage and race were added to the longitudinal model. F2-Isoprostane levels significantly increased in all girls over follow-up but this increase did not differ by family history of breast cancer, and the change was no longer significant our multivariate longitudinal analysis. Discussion: In both adult women and adolescent girls we found significant associations between oxidative stress and breast cancer risk. In adult women, low levels of urinary biomarkers of oxidative stress may promote cancer progression. During adolescence, girls with a family history of breast cancer may be exposed to higher rates of DNA oxidation that could result in genetic mutations. The relationships between oxidative stress, breast development, family history, and BMI should be the focus of future investigations.

O gastrópode terrestre Helix aspersa (Müller) é um herbívoro generalista, que habita a região mediterrânea. Os gastrópodes terrestres em geral entram em estados dormentes durante o seu ciclo de vida. A dormência é uma forma de inatividade associada a uma redução na taxa metabólica, sem grandes alterações no estado hídrico do animal (Withers & Cooper, 2010). Os gastrópodes terrestres quando saem de um estado dormente podem apresentar um aumento na produção de espécies reativas de oxigênio (ROS) nas mitocôndrias (Turrens et al., 1982) levando a um quadro de possível estresse oxidativo (Hermes-Lima & Zenteno-Savin, 2002). Cerca de 0,1% a 2% da respiração normal celular in vitro resulta em formação de ânion superóxido (Fridovich, 2004; Murphy, 2009; Hamanaka & Chandel, 2010). Muitos estudos apontam para um aumento na produção de ROS (Duranteau et al., 1998; Chandel et al., 1998; Wood et al., 1999; Killilea et al., 2000) durante a hipóxia. O estresse oxidativo é definido como o desequilíbrio no balanço entre agentes pró-oxidantes e agentes antioxidantes, em favor dos pró-oxidantes, levando a uma perturbação na sinalização e no controle redox e/ou dano molecular (Sies & Jones, 2007). A GSH é o principal grupo sulfidrila não proteico encontrado em células de mamíferos. Esta normalmente em uma concentração de 1 a 10 mM, enquanto a GSSG é encontrada em uma concentração de 10 a 100 vezes menor (Rossi et al., 1995; Griffith, 1999). A GSH atua desativando radicais livres, preservando o status redox celular e defendendo o organismo contra xenobióticos (Meister, 1995a). A ativação do sistema de defesa antioxidante, incluindo aumento da atividade de enzimas antioxidantes, durante situações de depressão metabólica foi chamada de preparo para o estresse oxidativo (Hermes-Lima et al., 1998). Esta ativação protege o organismo durante o hipometabolismo e durante a reoxigenação/despertar de um possível estresse oxidativo. Os objetivos deste estudo foram: analisar as possíveis respostas durante um ciclo de anoxia e reoxigenação do sistema de defesa antioxidante de Helix aspersa com níveis reduzidos de glutationa total (eq-GSH); e examinar a liberação de ROS em mitocôndrias isoladas de Helix aspersa em estivação. O metabolismo de GSH mostrou-se em nosso estudo como importante fator na manutenção do equilíbrio redox de Helix aspersa durante a anoxia e reoxigenação, lidando com um provável aumento de produção de ROS durante a reoxigenação. E durante a estivação, foi demonstrado que as mitocôndrias de glândula digestiva de Helix aspersa liberam mais H2O2 in vitro. Este aumento na liberação de ROS na mitocôndria pode estar relacionado com a indução de respostas antioxidantes, que ocorrem durante a estivação em gastrópodes terrestres em diversos estudos (Hermes-Lima & Storey, 1995; Ramos-Vasconcelos & Hermes-Lima, 2003; Ramos-Vasconcelos et al., 2005) / The gastropod Helix aspersa (Müller) is a generalist herbivore that inhabits the Mediterranean region. The terrestrial gastropods generally go into dormant states during their life cycle. Dormancy is a form of inactivity associated with a reduction in metabolic rate, without major changes in the water status of the animal (Withers & Cooper, 2010). The terrestrial gastropods when they leave a dormant state may experience an increased production of reactive oxygen species (ROS) in mitochondria (Turrens et al., 1982) leading to a potential oxidative stress (Hermes-Lima & Zenteno-Savin, 2002). About 0.1% to 2% of the normal cellular respiration in vitro results in formation of superoxide anion (Fridovich, 2004; Murphy, 2009; Hamanaka & Chandel, 2010). Many studies point to an increased production of ROS (Duranteau et al. 1998; Chandel et al., 1998, Wood et al. 1999; Killilea et al., 2000) during hypoxia. Oxidative stress is defined as the imbalance between pro-oxidant agents and antioxidants in favor of pro-oxidants, leading to a disruption of redox signaling and redox control and/or molecular damages (Sies & Jones, 2007). GSH is the main non-protein sulfhydryl group found in mammalian cells. It´s usually in a concentration of 1 to 10 mM, whereas GSSG is found at a concentration of 10 to 100 times lower (Rossi et al. 1995; Griffith, 1999). GSH acts by disabling free radicals, maintaining the cellular redox status and defending the body against xenobiotics (Meister, 1995a). The activation of the antioxidant defense system, including increased activity of antioxidant enzymes, during situations of metabolic depression is called \"preparation for oxidative stress (Hermes-Lima et al., 1998). This activation protects the body during hypometabolism and during recovery of a possible situation of oxidative stress. The objectives of this study were: to analyze the possible response during a cycle of anoxia and reoxygenation of the antioxidant defense system of Helix aspersa with reduced levels of total glutathione (GSH-eq) and to examine the release of ROS in isolated mitochondria from Helix aspersa in aestivation. The metabolism of GSH presented itself in our study as an important factor in maintaining the redox balance of Helix aspersa during anoxia and reoxygenation, dealing with a probable increase in ROS production during reoxygenation. And during aestivation, it was demonstrated that the digestive gland mitochondria of Helix aspersa released more H2O2 in vitro. This increased release of ROS in mitochondria may be related to induction of antioxidant responses that occur during aestivation in terrestrial gastropods in several studies (Hermes-Lima & Storey, 1995; Ramos-Vasconcelos & Hermes-Lima, 2003, Ramos- Vasconcelos et al., 2005)

Peroxiredoxins are small ubiquitous cysteine-containing proteins that exhibit high reactivity to hydrogen peroxide. Apart from their role as antioxidants, detoxifying hydrogen peroxide to water, peroxiredoxins have been implicated in other cellular processes, such as protein folding and signalling. Using S. cerevisiae as a model organism, we utilised a variety of techniques to examine previously unexplored links between peroxiredoxins and mitochondrial function. Firstly, we characterised the role of Gpx3 in yeast mitochondria. Proteomic work revealed the presence of Gpx3 in the mitochondrial intermembrane space (IMS) and we characterised when, how and why Gpx3 can be found within the mitochondria. We showed that cells lacking Gpx3 have aberrant mitochondrial morphology and defective protein import capacity and inner membrane potential upon H2O2 stress. Gpx3 translocates to the IMS via a targeting sequence encoded from a non-AUG codon. This provides a novel and unique molecular mechanism that protects mitochondria from the exceptional oxidative stress which their activity imposes. Secondly, we focused on the role of Tsa1 upon protein aggregation-induced stress. Previous studies using the proline analogue AZC to cause protein misfolding revealed that protein aggregates are localised adjacent to mitochondria and mitochondrial ROS are generated in response. We questioned what effect this might have on mitochondrial function and we showed that upon AZC treatment there is a drop in respiratory rate, dependent on Tsa1. We questioned whether Tsa1, like other peroxiredoxins, is involved in regulating signalling cascades and we showed that cells that are lacking Tsa1 have alterations in the activity of the cAMP/PKA pathway. In parallel, we looked for differences both in the proteome and the transcriptome to understand what is the cause of the lethality of a tsa1 strain upon protein aggregation stress. We propose a mechanism where Tsa1 mediates a transcriptional response to protein misfolding stress via the activity of the heat shock transcription factor, Hsf1. Finally, we focused on the role of the mitochondrial peroxiredoxin Prx1. Under conditions where the mitochondrial matrix is oxidised, either genetically or by chemical addition, we showed than an apoptotic pathway is activated, dependent on the redox state of thioredoxin, Trx3. We showed that Trx3 can interact with Prx1 and loss of Prx1 also stops the induction of cell death. Analysis of the interactome of Trx3 unraveled the involvement of Bxl1/Ybh3, the yeast BH3 domain-containing protein and Aim9, a previously uncharacterised protein with kinase-like motifs, in the progression of cell death. The data presented in this thesis widens our understanding of the function of peroxiredoxins and their involvement in the regulation of cellular cascades that ensure correct mitochondrial function and responses to stress.

Liu Ming Ju. / "June 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

by Angela Mara Bentes de Souza. / "June 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 176-200). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Posttranslational modification (PTM) of proteins is essential to creating a diverse proteome with the complex functions necessary to regulate key cellular processes. Redox-based PTMs exhibit many desirable characteristics to finely modulate transcriptional regulators; they occur rapidly and can alter protein conformation, localisation and activity. The plant immune system offers an excellent model in which to study redox-based modifications due to the rapid accumulation of oxidising agents that occurs during immune invasion. This so-called “oxidative burst” causes spontaneous oxidation of cysteine residues that are present in many regulatory proteins. These modifications fine-tune the activities of proteins that harbour them, enabling them to act in a concerted effort to reprogram the transcriptome, prioritising the expression of immune-related genes over housekeeping genes. Disulphide bonds (S-S) and S-nitrosothiols (SNO, i.e. the addition of an NO group to a cysteine moiety) have been shown to play particularly important roles in plant immunity. However, what still remains unclear is how these redox-based PTMs are rendered reversible, enabling them to act as molecular signalling switches. The work presented in this thesis explores a class of enzymes that are responsible for controlling the cellular levels of protein oxidation: the Thioredoxins. In addition to their well-established role in reducing disulphide bonds, I demonstrate in Chapter 3 that Thioredoxins are able to reverse protein S-nitrosylation during plant immune signalling. Immune-inducible Thioredoxin-h5 (TRXh5) was shown to be unable to restore immunity in gsnor1 mutants that display excessive accumulation of the NO donor S-nitrosoglutathione, but rescued impaired immunity and defence gene expression in nox1-mutants that exhibit elevated levels of free NO. This data indicates that TRXh5 discriminates between protein-SNO substrates to provide previously unrecognized specificity and reversibility to protein-SNO signalling in plant immunity. Furthermore, data is presented to show that TRXh5 reversed the effects of S.nitrosylation on many immune-related transcriptional regulators in vitro, forming the initial stages of an investigation into which proteins and pathways might be controlled by reversible S-nitrosylation in plant immunity (Chapters 3 & 4). Although the majority of transcriptional regulators are likely modified at their site of action, the nucleus, very little is currently known about nuclear redox signalling in plants. Therefore, in Chapter 5 a subclass of theThioredoxin superfamily was studied, the Nucleoredoxins, which have previously been shown to display disulphide reduction activity and localise in part to the nucleus. Here it is revealed that the activity and nuclear accumulation of Nucleoredoxin 1 (NRX1) is induced by the plant leaf pathogen Pseudomonas syringae, suggesting a key role for this protein in immune signalling. Target-capture experiments and subsequent mass spectrometry analysis identified the first in vitro targets of NRX1 and revealed many proteins with roles in oxidative stress, including the hydrogen peroxide scavenger Catalase 2 (CAT2). Moreover, overexpression of NRX1 was shown to be able to rescue the enhanced cell death phenotype of cat2 knockout mutants in response to the oxidative stressor, methyl viologen. Accordingly, nrx1 knockout mutants also exhibited an enhanced cell death phenotype in response to methyl viologen treatment. Together, these data indicate that NRX1 plays a key role in the control of oxidative stress-mediated cell death, potentially through direct regulation of Catalase proteins. Taken together, the work in this thesis implicates members of the Thioredoxin family as key regulators of transcriptional reprogramming during plant immunity and uncovers a novel role for Thioredoxin superfamily member, NRX1, in the control of oxidative stress.