A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress

Arkblad, Eva Lagberg; Tuck, Simon; Pestov, Nikolay B.; Dmitriev, Ruslan I.; Костина, М. Б.; Stenvall, Jörgen; Tranberg, Mattias; Rydström, Jan

doi:10.1016/j.freeradbiomed.2005.02.012

Cited by 101 publications

(56 citation statements)

References 32 publications

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“…The Trx/Prx and GSH systems require NADPH, which can be generated through multiple pathways in neuronal cells (45)(46)(47), and therefore, it was important to determine the link between Nnt activity to mitochondrial function and antioxidant activity in intact ROS-sensitive dopaminergic cells. Previous work in cell and animal models suggests that Nnt inhibition by siRNA transfection results in a more oxidized NADP ϩ /NADPH ratio accompanied by a more oxidized GSH/GSSG ratio (20,22,48). Indeed, Nnt inhibition by shRNA transfection resulted in a more oxidized NADP ϩ /NADPH ratio and an increase in GSSG and decrease in GSH levels (Fig.…”

Section: Parameter Ocr (Pmol/min)/(mg/ml)mentioning

confidence: 67%

Nicotinamide Nucleotide Transhydrogenase (Nnt) Links the Substrate Requirement in Brain Mitochondria for Hydrogen Peroxide Removal to the Thioredoxin/Peroxiredoxin (Trx/Prx) System

Lopert

Patel

2014

Journal of Biological Chemistry

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Background: Actively respiring brain mitochondria can consume H 2 O 2 through thioredoxin/peroxiredoxin (Trx/Prx). Results: Inhibition of nicotinamide nucleotide transhydrogenase (Nnt) decreases NADPH levels, decreases Trx and Trx reductase activity, and increases toxicity to oxidative stress. Conclusion: Nnt links mitochondrial respiration and antioxidant activity in brain mitochondria. Significance: Nnt may be a therapeutic target to increase the antioxidant activity in cells.

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Section: Parameter Ocr (Pmol/min)/(mg/ml)mentioning

confidence: 67%

Nicotinamide Nucleotide Transhydrogenase (Nnt) Links the Substrate Requirement in Brain Mitochondria for Hydrogen Peroxide Removal to the Thioredoxin/Peroxiredoxin (Trx/Prx) System

Lopert

Patel

2014

Journal of Biological Chemistry

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“…NNT supplies the high concentrations of NADPH needed for glutathione and thioredoxin antioxidant systems involving enzymes such as GPX1 (glutathione peroxidase 1), TXNRD2 and PRDX3 (peroxiredoxin 3). NADPH is a cofactor of P450 enzymes, notably in steroidogenesis (19,20,21,22) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

Roucher‐Boulez

Mallet-Motak

Samara-Boustani³

et al. 2016

European Journal of Endocrinology

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Objective: Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages. Methods: Sanger or massive parallel sequencing of NNT and patient monitoring. Results: Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8-18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed. Conclusions: NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.

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“…The Tg Worms and glb-13 Mutants Did Not Show Altered Antioxidant Enzymes Level SOD, catalase, and glutathione play important roles for detoxification of ROS in C. elegans (31)(32)(33). We propose that hNgb might directly scavenge free radicals similar to SOD and/or may upregulate several key antioxidant enzymes to exert its action.…”

Section: The Tg Worms and Glb-13 Mutants Have No Deviant Fluorescein mentioning

confidence: 93%

GLB‐13 is associated with oxidative stress resistance in caenorhabditis elegans

Ren

Han

et al. 2013

IUBMB Life

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Globins constitute a superfamily of heme-binding proteins that is widely present in many species. There are 33 putative globins in the genome of Caenorhabditis elegans, where glb-13 is a homolog of neuroglobin (Ngb) based on sequence analysis and specific expression in neurons. Here we examined whether glb-13 as well as Ngb is also associated with resistance to reactive oxygen species (ROS) induced by paraquat. Our results showed that the mRNA level of glb-13 was significantly upregulated after paraquat exposure. Expression of a green fluorescent protein (GFP) reporter gene directed by the glb-13 promoter was increased by paraquat exposure. The mutant C. elegans strain glb-13(tm2825) was sensitive to paraquat-induced oxidative stress. Overexpression of human Ngb (hNgb) in C. elegans neuronal cells can rescue the paraquat sensitive phenotype of the mutant strain. glb-13 mutation or hNgb overexpression did not affect the expression of antioxidant enzymes such as superoxide dismutase (SOD). To examine the ROS-scavenging capabilities of hNgb and glb-13, we further examined the level of ROS in glb-13 mutant and hNgb transgenic (hNgb-Tg) worms. There was no statistical difference in ROS levels in the untreated controls; however in paraquattreated worms, the ROS level was statistically repressed in the hNgb-Tg relative to enhanced green fluorescent protein (EGFP)-Tg worms or wildtype animals. Additionally, the ROS level of glb-13 mutant was statistically higher than the wildtype animals. Furthermore, hNgb overexpression diminished the ROS level of glb-13 mutant. In conclusion, hNgb can rescue the ROS sensitive phenotype of the glb-13 mutant strain. The protein GLB-13 seems to have an hNgb-like function, suggesting the importance of the globin protein family in maintaining the homeostasis of ROS signals. Our data provided evidence for the first time that glb-13 is associated with the resistance against oxidative stress-induced toxicity.

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A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress

Cited by 101 publications

References 32 publications

Nicotinamide Nucleotide Transhydrogenase (Nnt) Links the Substrate Requirement in Brain Mitochondria for Hydrogen Peroxide Removal to the Thioredoxin/Peroxiredoxin (Trx/Prx) System

Nicotinamide Nucleotide Transhydrogenase (Nnt) Links the Substrate Requirement in Brain Mitochondria for Hydrogen Peroxide Removal to the Thioredoxin/Peroxiredoxin (Trx/Prx) System

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

GLB‐13 is associated with oxidative stress resistance in caenorhabditis elegans

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