The regeneration of reduced glutathione in rat forebrain mitochondria identifies metabolic pathways providing the NADPH required

Vogel, Roland; Wiesinger, Heinrich; Hamprecht, Bernd; Dringen, Ralf

doi:10.1016/s0304-3940(99)00748-x

Cited by 110 publications

(89 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 68%

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

View full text Add to dashboard Cite

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.

show abstract

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

confidence: 68%

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

View full text Add to dashboard Cite

show abstract

“…Indeed, it deacetylates and activates several enzymes critical in maintaining cellular ROS levels such as SOD2, so that the catalytic activity of the enzyme is diminished when Sirt3 is deleted . SIRT3 also stimulates the activity of mitochondrial isocitrate dehydrogenase, IDH2, (Someya et al 2010), which, via energy-dependent transhydrogenation (Vogel et al 1999) promotes NADH-supported NADP + reduction to NADPH, which in turn provides the reducing equivalents for conversion of oxidized to reduced glutathione. Based on these results, the possibility that angiotensin II-induced IR is due to mitochondrial ROS generation causally linked to Sirt3 dysregulation has been investigated (Macconi et al 2015).…”

Section: Mechanisms Of H 2 O 2 Generationmentioning

confidence: 99%

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Meo

Iossa

Venditti

2017

Journal of Endocrinology

222

103

View full text Add to dashboard Cite

At present, obesity is one of the most important public health problems in the world because it causes several diseases and reduces life expectancy. Although it is well known that insulin resistance plays a pivotal role in the development of type 2 diabetes mellitus (the more frequent disease in obese people) the link between obesity and insulin resistance is yet a matter of debate. One of the most deleterious effects of obesity is the deposition of lipids in non-adipose tissues when the capacity of adipose tissue is overwhelmed. During the last decade, reduced mitochondrial function has been considered as an important contributor to 'toxic' lipid metabolite accumulation and consequent insulin resistance. More recent reports suggest that mitochondrial dysfunction is not an early event in the development of insulin resistance, but rather a complication of the hyperlipidemia-induced reactive oxygen species (ROS) production in skeletal muscle, which might promote mitochondrial alterations, lipid accumulation and inhibition of insulin action. Here, we review the literature dealing with the mitochondria-centered mechanisms proposed to explain the onset of obesity-linked IR in skeletal muscle. We conclude that the different pathways leading to insulin resistance may act synergistically because ROS production by mitochondria and other sources can result in mitochondrial dysfunction, which in turn can further increase ROS production leading to the establishment of a harmful positive feedback loop.

show abstract

“…Although THD is not the only source of NADPH in mitochondria (the NADP-isocitrate dehydrogenase and the malic enzyme are also potential sources (37,38,53)), the negative redox potentials of the large NADH pool and the smaller NADPH pool (see plot of NADPH redox potential in inset of Fig. 5) represent strong thermodynamic driving forces for keeping the GSH/GSSG ratio high through the NADPH-dependent GR (Fig.…”

Section: Effects Of Fixed Cytosolic Gsh/gssg Ratios On Mitochondria Imentioning

confidence: 99%

Sequential Opening of Mitochondrial Ion Channels as a Function of Glutathione Redox Thiol Status

Aon

Cortassa

Maack³

et al. 2007

Journal of Biological Chemistry

182

236

View full text Add to dashboard Cite

Mitochondrial membrane potential (⌬⌿ m ) depolarization contributes to cell death and electrical and contractile dysfunction in the post-ischemic heart. An imbalance between mitochondrial reactive oxygen species production and scavenging was previously implicated in the activation of an inner membrane anion channel (IMAC), distinct from the permeability transition pore (PTP), as the first response to metabolic stress in cardiomyocytes. The glutathione redox couple, GSH/GSSG, oscillated in parallel with ⌬⌿ m and the NADH/NAD ؉ redox state. Here we show that depletion of reduced glutathione is an alternative trigger of synchronized mitochondrial oscillation in cardiomyocytes and that intermediate GSH/GSSG ratios cause reversible ⌬⌿ m depolarization, although irreversible PTP activation is induced by extensive thiol oxidation. Mitochondrial dysfunction in response to diamide occurred in stages, progressing from oscillations in ⌬⌿ m to sustained depolarization, in association with depletion of GSH. Mitochondrial oscillations were abrogated by 4-chlorodiazepam, an IMAC inhibitor, whereas cyclosporin A was ineffective. In saponin-permeabilized cardiomyocytes, the thiol redox status was systematically clamped at GSH/GSSG ratios ranging from 300:1 to 20:1. At ratios of 150:1-100:1, ⌬⌿ m depolarized reversibly, and a matrix-localized fluorescent marker was retained; however, decreasing the GSH/GSSG to 50:1 irreversibly depolarized ⌬⌿ m and induced maximal rates of reactive oxygen species production, NAD(P)H oxidation, and loss of matrix constituents. Mitochondrial GSH sensitivity was altered by inhibiting either GSH uptake, the NADPH-dependent glutathione reductase, or the NADH/NADPH transhydrogenase, indicating that matrix GSH regeneration or replenishment was crucial. The results indicate that GSH/GSSG redox status governs the sequential opening of mitochondrial ion channels (IMAC before PTP) triggered by thiol oxidation in cardiomyocytes.The dual nature of oxygen as a vital electron acceptor in oxidative phosphorylation and as a dangerously reactive molecule has created pressure for the cell to evolve powerful antioxidant defenses that convert reactive oxygen species (ROS) 3 into harmless products to maintain a predominantly reduced redox environment. This depends on the following two factors: the reduction potential of the electron carriers, and the reducing capacity (i.e. the total concentration of the reduced species) of linked redox couples present in the cytoplasm or in the intraorganellar compartments (e.g. the mitochondrial matrix) of the cell. In addition to the redox couples involved in mitochondrial electron transport (the nicotinamide adenine dinucleotides NADH/NAD ϩ , and the flavins FADH 2 / FAD), the three main cellular redox pairs participating in intracellular reactions include reduced/oxidized glutathione (GSH/GSSG), thioredoxin (Trx(SH) 2 /TrxSS), and NADPH/ NADP ϩ , with the latter providing the thermodynamic driving force behind the glutathione and thioredoxin systems (1). The GSH/GSSG pool is the ...

show abstract

The regeneration of reduced glutathione in rat forebrain mitochondria identifies metabolic pathways providing the NADPH required

Cited by 110 publications

References 17 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

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Sequential Opening of Mitochondrial Ion Channels as a Function of Glutathione Redox Thiol Status

Contact Info

Product

Resources

About