Repair of peroxynitrite damage to tubulin by the thioredoxin reductase system

Landino, Lisa M.; Iwig, Jeffrey S.; Kennett, Kelly L; Moynihan, Katherine L.

doi:10.1016/j.freeradbiomed.2003.11.026

Cited by 38 publications

(40 citation statements)

References 35 publications

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“…It has been shown that enzymes of glycolysis and of the Krebs cycle can be S-glutathionylated under oxidative stress (Supplementary Table 2; Fratelli et al 2004). Noteworthy, tubulin, the major component of the sperm flagellum, can be modified by tyrosine nitration and S-glutathionylation (Landino et al 2004); thus, our results suggest that sperm motility is affected also at the level of flagellar structure.…”

Section: Discussionmentioning

confidence: 54%

Oxidative stress impairs function and increases redox protein modifications in human spermatozoa

Morielli¹,

2015

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Oxidative stress, generated by excessive reactive oxygen species (ROS) or decreased antioxidant defenses (and possibly both), is associated with male infertility. Oxidative stress results in redox-dependent protein modifications, such as tyrosine nitration and S-glutathionylation. Normozoospermic sperm samples from healthy individuals were included in this study. Samples were incubated with increasing concentrations (0-5 mM) of exogenous hydrogen peroxide, tert-butyl hydroperoxide, or diethylamine NONOate (DA-NONOate, a nitric oxide (NO%) donor) added to the medium. Spermatozoa treated with or without ROS were incubated under capacitating conditions and then levels of tyrosine phosphorylation and percentage of acrosome reaction (AR) induced by lysophosphatidylcholine were determined. Modified sperm proteins from cytosolic, triton-soluble, and triton-insoluble fractions were analyzed by SDS-PAGE immunoblotting and immunocytochemistry with anti-glutathione and anti-nitrotyrosine antibodies. Levels of S-glutathionylation increased dose dependently after exposure to hydroperoxides (P!0.05) and were localized mainly to the cytosolic and triton-soluble fractions of the spermatozoa. Levels of tyrosine-nitrated proteins increased dose dependently after exposure to DA-NONOate (P!0.05) and were mainly localized to the triton-insoluble fraction. ROS-treated spermatozoa showed impaired motility without affecting viability (hypo-osmotic swelling test). These treated spermatozoa had tyrosine phosphorylation and AR levels similar to that of non-capacitated spermatozoa following incubation under capacitating conditions, suggesting an impairment of sperm capacitation by oxidative stress. In conclusion, oxidative stress promotes a dose-dependent increase in tyrosine nitration and S-glutathionylation and alters motility and the ability of spermatozoa to undergo capacitation. Free Spanish abstractA Spanish translation of this abstract is freely available at

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Section: Discussionmentioning

confidence: 54%

Oxidative stress impairs function and increases redox protein modifications in human spermatozoa

Morielli¹,

2015

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“…In another study, peroxynitrate (100 mmol=L) inhibited platelet aggregation of washed platelets and depleted low molecular weight thiols such as glutathione, probably by two-electron oxidation leading to disulfide formation (209,213). Peroxynitrite also induces disulfide bonds between the a and b tubulin subunits (b1 tubulin is a structural protein in platelets (218)) a reaction found to be repaired by thioredoxin in cells (155).…”

Section: F Potential Modification Of Platelet Thiols By Peroxynitritementioning

confidence: 99%

Redox Control of Platelet Function

Essex¹

2009

Antioxidants & Redox Signaling

102

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There has recently been a dramatic expansion in research in the area of redox biology with systems that utilize thiols to perform redox chemistry being central to redox control. Thiol-based reactions occur in proteins involved in platelet function, including extracellular platelet proteins. The alphaIIbbeta3 fibrinogen receptor contains free thiols that are required for the activation of this receptor to a fibrinogen-binding conformation. This process is under enzymatic control, with protein disulfide isomerase playing a central role in the activation of alphaIIbbeta3. Other integrins, such as the alpha2beta1 collagen receptor on platelets, are also regulated by protein disulfide isomerase and thiol metabolism. Low molecular weight thiols that are found in blood regulate these processes by converting redox sensitive disulfide bonds to thiols and by providing the appropriate redox potential for these reactions. Additional mechanisms of redox control of platelets involve nitric oxide that inhibits platelet responses, and reactive oxygen species that potentiate platelet thrombus formation. Specific nitrosative or oxidative modifications of thiol groups in platelets may modulate platelet function. Since many biologic processes are regulated by redox reactions that involve surface thiols, the extracellular redox state can have an important influence on health and disease status and may be a target for therapeutic intervention.

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“…Tubulin and tau are crucial components of microtubules important for the neuronal cytoskeleton. Interestingly, damage to tubulins is repaired by thioredoxin reductases [Landino et al, 2004]. The gene-encoding thiredoxin reductase 3 is downregulated in Dhcr7-/-mice.…”

Section: Neuronal Cytoskeleton Instability and Neurodegeneration As Amentioning

confidence: 99%

Immunohistochemical and Microarray Analyses of a Mouse Model for the Smith-Lemli-Opitz Syndrome

et al. 2005

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The Smith-Lemli-Opitz syndrome is a mental retardation/malformation syndrome with behavioral components of autism. It is caused by a deficiency in 3β-hydroxysteroid-Δ⁷-reductase (DHCR7), the enzyme required for the terminal enzymatic step of cholesterol biosynthesis. The availability of Smith-Lemli-Opitz syndrome mouse models has made it possible to investigate the genesis of the malformations associated with this syndrome. Dhcr7 gene modification (Dhcr7–/–) results in neonatal lethality and multiple organ system malformations. Pathology includes cleft palate, pulmonary hypoplasia, cyanosis, impaired cortical response to glutamate, and hypermorphic development of hindbrain serotonergic neurons. For the current study, hindbrain regions microdissected from gestational day 14 Dhcr7–/–, Dhcr7+/– and Dhcr7+/+ fetuses were processed for expression profiling analyses using Affymetrix oligonucleotide arrays and filtered using statistical significance (S-score) of change in gene expression. Of the 12,000 genes analyzed, 91 were upregulated and 98 were downregulated in the Dhcr7–/– hindbrains when compared to wild-type animals. Fewer affected genes, representing a reduced affect on these pathways, were identified in heterozygous animals. Hierarchical clustering identified altered expression of genes associated with cholesterol homeostasis, cell cycle control and apoptosis, neurodifferentiation and embryogenesis, transcription and translation, cellular transport, neurodegeneration, and neuronal cytoskeleton. Of particular interest, Dhcr7 gene modification elicited dynamic changes in genes involved in axonal guidance. In support of the microarray findings, immunohistochemical analyses of the netrin/deleted in colorectal cancer axon guidance pathway illustrated midline commissural deficiencies and hippocampal pathfinding errors in Dhcr7–/– mice. The results of these studies aid in providing insight into the genesis of human cholesterol-related birth defects and neurodevelopmental disorders and highlight specific areas for future investigation.

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Repair of peroxynitrite damage to tubulin by the thioredoxin reductase system

Cited by 38 publications

References 35 publications

Oxidative stress impairs function and increases redox protein modifications in human spermatozoa

Oxidative stress impairs function and increases redox protein modifications in human spermatozoa

Redox Control of Platelet Function

Immunohistochemical and Microarray Analyses of a Mouse Model for the Smith-Lemli-Opitz Syndrome

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