Evidence That the Rat Hepatic Mitochondrial Carrier Is Distinct from the Sinusoidal and Canalicular Transporters for Reduced Glutathione

Garcı́a-Ruiz, Carmen; Morales, Albert; Colell, Anna; Rodés, Joan; Yi, Jine; Kaplowitz, Neil; Fernández-Checa, José C.

doi:10.1074/jbc.270.27.15946

Cited by 48 publications

(36 citation statements)

References 24 publications

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“…Thus, mitochondrial GSH status will be a critical modulator of mitochondrial function and cell viability and, hence, in diseases and/or tissue injury mediated by oxidative stress in mitochondria, mitochondrial GSH depletion will accentuate the adverse effects of ROS (10,24,25,27,43,45,46). Since mitochondrial GSH arises by the existence of an ATP-dependent carrier, which translocates cytosol GSH into the matrix, it would be critical to characterize its nature and properties at a molecular level (47).…”

Section: Mitochondrial Gsh Depletion Results In Loss Of Mitochondrialmentioning

confidence: 99%

Direct Effect of Ceramide on the Mitochondrial Electron Transport Chain Leads to Generation of Reactive Oxygen Species

Garcı́a-Ruiz¹,

Colell²,

Marı́³

et al. 1997

Journal of Biological Chemistry

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757

555

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Ceramide is a sphingolipid that is generated in the signaling of inflammatory cytokines such as tumor necrosis factor (TNF), which exerts many functional roles depending on the cell type where it is produced. Since TNF cytotoxicity is mediated by overproduction of reactive oxygen species from mitochondria, we have examined the role of ceramide in generation of oxidative stress in isolated rat liver mitochondria. The present studies demonstrate that addition of N-acetylsphingosine (C 2 -ceramide) to mitochondria led to an increase of fluorescence of dihydrorhodamine 123 or dichlorofluorescein-stained mitochondria, indicating formation of hydrogen peroxide. Such effect was significant at 0.25 M and maximal at 1-5 M C 2 , decreasing at greater concentrations. This inductive effect of ceramide was mimicked by N-hexanoylsphingosine at the same concentration range, whereas the immediate precursor of C 2 , C 2 -dihydroceramide increased hydrogen peroxide at 1-5 M. Sphingosine generated hydrogen peroxide at concentrations 10 M, whereas diacylglycerol failed to increase hydrogen peroxide. The increase in hydrogen peroxide induced by C 2 was not triggered by mitochondrial permeability transition as C 2 did not induce mitochondrial swelling. Blocking electron transport chain at complex I and II prevented the increase in hydrogen peroxide induced by C 2 ; however, interruption of electron flow at complex III by antimycin A potentiated the inductive effect of C 2 . Depletion of matrix GSH prior to exposure to ceramide resulted in a potentiated increase (2-fold) of hydrogen peroxide generation, leading to lipid peroxidation and loss of activity of respiratory chain complex IV compared with GSH-repleted mitochondria. Mitochondria isolated from TNF-treated cells showed an increase (2-3-fold) in the amount of ceramide compared with mitochondria from untreated cells. These results suggest that mitochondria are a target of ceramide produced in the signaling of TNF whose effect on mitochondrial electron transport chain leads to overproduction of hydrogen peroxide and consequently this phenomena may account for the generation of reactive oxygen species during TNF cytotoxicity.

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Section: Mitochondrial Gsh Depletion Results In Loss Of Mitochondrialmentioning

confidence: 99%

Direct Effect of Ceramide on the Mitochondrial Electron Transport Chain Leads to Generation of Reactive Oxygen Species

Garcı́a-Ruiz¹,

Colell²,

Marı́³

et al. 1997

Journal of Biological Chemistry

Self Cite

757

555

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“…Since GSH, not synthesized in mitochondria, must be synthesized in the cytosol and transported into mitochondria by a specific transporter. 18 It is then anticipated that GSH reserve in mitochondria themselves may be limited. It can be expected the GSH reserve in mitochondria can be rapidly depleted when excessive mROS generated surpasses the GSH-mediated buffering capacity of this organelle.…”

Section: Resultsmentioning

confidence: 99%

“…[40][41][42][43][44][45][46] Furthermore, GSH, not synthesized in mitochondria, must be synthesized in the cytosol and transported into mitochondria by a specific transporter. 18 Along the same vein, the oxidized GSSG is not retransported into the cytosol for its reduction to GSH. 47 Therefore, mitochondrial NADPH, mediated by the enzyme isocitrate dehydrogenase (ICDH), but not glucose-6-phosphate dehydrogenase (G6PD), is necessary for the regeneration of GSH from GSSG catalyzed via mitochondrial GSH reductase.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant hep G2 cells through a mitochondria-dependent oxidative stress mechanism

Chiou¹,

Tai²,

Wang³

et al. 2009

Cancer Biology & Therapy

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“…Third, depletion of mitochondrial, but not cytosolic, GSH potentiated the oxidative cell death after treatment with tertbutyl hydroperoxide (53). Fourth, GSH, not synthesized in mitochondria, must be synthesized in the cytosol and transported into mitochondria by a specific transporter (19,54). Fifth, the oxidized GSSG is not retransported into the cytosol for its reduction to GSH (21).…”

Section: Discussionmentioning

confidence: 99%

Control of Mitochondrial Redox Balance and Cellular Defense against Oxidative Damage by Mitochondrial NADP+-dependent Isocitrate Dehydrogenase

Jo¹,

Son²,

Koh³

et al. 2001

Journal of Biological Chemistry

482

365

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Mitochondria are the major organelles that produce reactive oxygen species (ROS) and the main target of ROS-induced damage as observed in various pathological states including aging. Production of NADPH required for the regeneration of glutathione in the mitochondria is critical for scavenging mitochondrial ROS through glutathione reductase and peroxidase systems. We investigated the role of mitochondrial NADP ؉ -dependent isocitrate dehydrogenase (IDPm) in controlling the mitochondrial redox balance and subsequent cellular defense against oxidative damage. We demonstrate in this report that IDPm is induced by ROS and that decreased expression of IDPm markedly elevates the ROS generation, DNA fragmentation, lipid peroxidation, and concurrent mitochondrial damage with a significant reduction in ATP level. Conversely, overproduction of IDPm protein efficiently protected the cells from ROS-induced damage. The protective role of IDPm against oxidative damage may be attributed to increased levels of a reducing equivalent, NADPH, needed for regeneration of glutathione in the mitochondria. Our results strongly indicate that IDPm is a major NADPH producer in the mitochondria and thus plays a key role in cellular defense against oxidative stress-induced damage.Cell damage induced by oxidative stress and reactive oxygen species (ROS) 1 has been implicated in several human diseases including aging, alcohol-mediated organ damage, neurodegenerative diseases, many types of cancers, cardiovascular diseases, and UV-mediated skin disorders (1). As one of the major sources of ROS (2), mitochondria are highly susceptible to oxidative damage. ROS can damage mitochondrial enzymes directly (3), and they can cause mutation in mitochondrial DNAs (4). At the same time, ROS can change the mitochondrial transmembrane potential (⌬m), which is indicative of mitochondrial membrane integrity (5) and precedes cell death induced by various toxic compounds and cytokines (6). Recent reports indicate that mitochondrial ROS cause apoptosis (7, 8) by activating various apoptotic effectors such as cytochrome c release, procaspase-2, procaspase-9, procaspase-3, and latent apoptosis-inducing factor, which is released from the mitochondria during apoptosis (9 -11). Another report also suggested that mitochondrial ROS directly caused apoptosis of T cells (12). It was also reported that tumor necrosis factor ␣ causes a rapid production of mitochondrial ROS (13) and that ceramide, an apoptotic stimulus, also plays a crucial role in tumor necrosis factor ␣-induced mitochondrial ROS generation (14). Furthermore, several other investigators demonstrated that ROS are involved in the signaling pathway of certain growth factors (15) and cytokines (16). In addition, mitochondrial ROS, under hypoxic conditions, activate the transcription of the genes for glycolytic enzymes as well as erythropoietin and vascular endothelial growth factor by upregulating a transcriptional factor, hypoxia-inducible factor 1 (17), suggesting that mitochondrial ROS mediate cross-talk b...

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Evidence That the Rat Hepatic Mitochondrial Carrier Is Distinct from the Sinusoidal and Canalicular Transporters for Reduced Glutathione

Cited by 48 publications

References 24 publications

Direct Effect of Ceramide on the Mitochondrial Electron Transport Chain Leads to Generation of Reactive Oxygen Species

Direct Effect of Ceramide on the Mitochondrial Electron Transport Chain Leads to Generation of Reactive Oxygen Species

Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant hep G2 cells through a mitochondria-dependent oxidative stress mechanism

Control of Mitochondrial Redox Balance and Cellular Defense against Oxidative Damage by Mitochondrial NADP+-dependent Isocitrate Dehydrogenase

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