The Mitochondrial Thioredoxin System

Miranda‐Vizuete, Antonio; Damdimopoulos, Anastasios; Spyrou, Giannis

doi:10.1089/ars.2000.2.4-801

Cited by 138 publications

(83 citation statements)

References 73 publications

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“…Oxygen free radicals are potent executors of cell death associated with pro-inflammatory cytokine effects and are known to be involved in b cell destruction in type 1 diabetes (Verge et al 1995, Rabinovitch et al 1999, Chang et al 2004. PRX III acts as an effective guardian against excessive oxygen radical generation in mitochondria (Miranda-Vizuete et al 2000, Nonn et al 2003, Chang et al 2004. In our experiments with cells over-expressing PRX III, we were not able to detect a significant accumulation of ROS after stress with H 2 O 2 or any effect by induction with doxycyclin.…”

Section: Discussionmentioning

confidence: 99%

Peroxiredoxin III protects pancreatic β cells from apoptosis

Wolf

Aumann²,

Michalska³

et al. 2010

Journal of Endocrinology

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Type 1 diabetes mellitus is characterized by a progressive autoimmune destruction of insulin-producing b cells. Macrophages and T lymphocytes release cytokines, which induce the synthesis of oxygen and nitrogen radicals in the pancreatic islets. The resulting cellular and mitochondrial damage promotes b cell death. b cells are very sensitive to the autoimmune free radical-dependent attack due to their low content of antioxidant enzymes such as glutathione peroxidase and catalase. A focal point of b cell protection should be the control of the mitochondrial redox status, which will result in the preservation of metabolic stimulus-secretion coupling. For this reason, there is a considerable interest in the mitochondrial peroxiredoxin III (PRX III), a thioredoxindependent peroxide reductase, which was shown to be able to protect against both oxidative and nitrosative stress.Using the Tet-On-system, we generated stably transfected rat insulinoma cells over-or under-expressing PRX III in a doxycyclin-dependent manner to analyze the effect of increased or decreased amounts of cellular PRX III, following treatment with several stressors. We provide evidence that PRX III protects pancreatic b cells from cell stress induced by accumulation of hydrogen peroxide, or the induction of inducible nitric oxide synthase or caspase-9 and -3 by pro-inflammatory cytokines or streptozotocin. Basal insulin secretion was markedly decreased in cells expressing lower levels of PRX III. We suggest PRX III may be a suitable target for promoting deceleration or even prevention of stress-associated apoptosis in pancreatic b cells and the manifestation of insulin-dependent diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Peroxiredoxin III protects pancreatic β cells from apoptosis

Wolf

Aumann²,

Michalska³

et al. 2010

Journal of Endocrinology

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“…The unforeseen result of the sperm-specific localization of human Sptrx prompted us to investigate whether other members of the two thioredoxin systems (cytosolic and mitochondrial) (3,25) as well as a newly identified thioredoxin reductase highly expressed in testis (26) are present in these cells. We used specific antibodies against all of these proteins, and by Western blot analysis we were able to identify all of them in both human testis and sperm extracts (Fig.…”

Section: Tissue Expression and Cellular And Subcellular Localizationmentioning

confidence: 99%

“…In mammals, cytosolic Trx has been shown to be an antioxidant; a modulator of apoptosis, cell growth, and differentiation; and also a regulator of the DNA-binding activity of several transcription factors (following translocation into the nucleus), while the function of the mitochondrial thioredoxin system has not yet been elucidated although it is thought to constitute a major antioxidant defense mechanism. A common characteristic of both mammalian systems is their ubiquitous presence in all of the tissues investigated within the same organism (3,4). The human spermatozoon provides the male pronucleus for fertilization, and to achieve this objective it has developed a highly specialized morphology organized into two major structures: the head and the tail or flagellum (5).…”

mentioning

confidence: 99%

Characterization of Sptrx, a Novel Member of the Thioredoxin Family Specifically Expressed in Human Spermatozoa

Miranda‐Vizuete

Ljung

Damdimopoulos

et al. 2001

Journal of Biological Chemistry

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137

124

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Thioredoxins (Trx) are small ubiquitous proteins that participate in different cellular processes via redox-mediated reactions. We report here the identification and characterization of a novel member of the thioredoxin family in humans, named Sptrx (sperm-specific trx), the first with a tissue-specific distribution, located exclusively in spermatozoa. Sptrx open reading frame encodes for a protein of 486 amino acids composed of two clear domains: an N-terminal domain consisting of 23 highly conserved repetitions of a 15-residue motif and a C-terminal domain typical of thioredoxins. Northern analysis and in situ hybridization shows that Sptrx mRNA is only expressed in human testis, specifically in round and elongating spermatids. Immunostaining of human testis sections identified Sptrx protein in spermatids, while immunofluorescence and immunogold electron microscopy analysis demonstrated Sptrx localization in the cytoplasmic droplet of ejaculated sperm. Sptrx appears to have a multimeric structure in native conditions and is able to reduce insulin disulfide bonds in the presence of NADPH and thioredoxin reductase. During mammalian spermiogenesis in testis seminiferous tubules and later maturation in epididymis, extensive reorganization of disulfide bonds is required to stabilize cytoskeletal sperm structures. However, the molecular mechanisms that control these processes are not known. The identification of Sptrx with an expression pattern restricted to the postmeiotic phase of spermatogenesis, when the sperm tail is organized, suggests that Sptrx might be an important factor in regulating critical steps of human spermiogenesis. Thioredoxins (Trx)1 are low molecular weight proteins (12 kDa) that catalyze thiol-disulfide redox reactions by the reversible oxidation of the cysteine residues of their conserved active site WCGPC (1). Thioredoxins are maintained in their active reduced form by the flavoenzyme thioredoxin reductase that uses the reducing power of NADPH, which constitutes the so-called thioredoxin system (2). All of the organisms from bacteria to humans appear to have at least one complete thioredoxin system, and the progressive complexity of eukaryotic organisms is also reflected in the increasing number of thioredoxin systems. Thus, Escherichia coli contains two thioredoxins and one thioredoxin reductase; yeast has two thioredoxin systems, one in cytosol and the other one in mitochondria; and photosynthetic organisms have several thioredoxin systems in different cellular compartments including chloroplasts. Finally, mammalian cells have at least two thioredoxin systems located in the cytosol and mitochondria, respectively (3). Different functions have been assigned to thioredoxins relying mostly on their general disulfide-reductase activity. In mammals, cytosolic Trx has been shown to be an antioxidant; a modulator of apoptosis, cell growth, and differentiation; and also a regulator of the DNA-binding activity of several transcription factors (following translocation into the nucleus), while the func...

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“…The redox environment of mitochondria is controlled, in part, by reductants such as NAD(P)H, ascorbate, and glutathione (GSH). In addition, GSH and thioredoxin-dependent enzymes play a major role in maintaining reducing equivalents required for enzyme function and signal transduction [13,14]. An age-related decline in any of these systems would likely result in an enhanced pro-oxidant environment and subsequent oxidative injury to critical mitochondrial proteins.…”

Section: Introductionmentioning

confidence: 99%

Two subpopulations of mitochondria in the aging rat heart display heterogenous levels of oxidative stress

Suh

Heath

Hagen

2003

Free Radical Biology and Medicine

109

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Cardiac mitochondria are composed of two distinct subpopulations: one beneath the sarcolemma (subsarcolemmal mitochondria: SSM), and another along the myofilaments (interfibrillary mitochondria: IFM). Previous studies suggest a preferential loss of IFM function with age; however, the age-related changes in oxidative stress in these mitochondrial subpopulations have not been examined. To this end, the changes in mitochondrial antioxidant capacity, oxidant output, and oxidative damage to Complex IV in IFM and SSM from young and old rats were studied. Results show no apparent differences in any parameters examined between IFM and SSM from young rats. However, relative to young, only IFM from old rats had a significantly higher rate of oxidant production and a decline in mitochondrial ascorbate levels and GSH redox status. The age-related decline in mitochondrial antioxidant capacity in IFM was accompanied by a marked loss in glutaredoxin and GSSG reductase activities, suggesting a diminished reductive capacity in IFM with age. Moreover, the loss in Complex IV activity was limited to the IFM of old rats, which was accompanied by a 4-fold increase in 4-hydroxynonenal-modified Complex IV. Thus, mitochondrial decay is not uniform and further indicates that myofibrils may be uniquely under oxidative stress in the aging heart.

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The Mitochondrial Thioredoxin System

Cited by 138 publications

References 73 publications

Peroxiredoxin III protects pancreatic β cells from apoptosis

Peroxiredoxin III protects pancreatic β cells from apoptosis

Characterization of Sptrx, a Novel Member of the Thioredoxin Family Specifically Expressed in Human Spermatozoa

Two subpopulations of mitochondria in the aging rat heart display heterogenous levels of oxidative stress

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