Mitochondrial Glutathione: Regulation and Functions

Calabrese, Gaetano; Morgan, Bruce; Riemer, Jan

doi:10.1089/ars.2017.7121

Cited by 139 publications

(92 citation statements)

References 137 publications

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“…The GSH/ GSSG ratio in the cytosol is typically ‡30:1-100:1 with a redox potential of -290 mV; this ratio in the mitochondria is estimated to be >100:1 with a redox potential of £ -300 mV. By contrast, this ratio appears to be 1:1 to 3:1 in the ER with a redox potential of -175 to -185 mV, which accounts for the relatively oxidizing environment of the ER (9,25,75,88).…”

Section: Cellular Distribution Of the Gsh/gssg Couplementioning

confidence: 95%

“…5). The a-KG carrier (encoded by SLC25A11) and the dicarboxylate transport mechanisms (dicarboxylate carrier, encoded by SLC25A10) are two potential candidates for importing cytosolic GSH to the mitochondria, mainly in the kidney and liver; the tricarboxylate carrier (encoded by SLC25A1) is a potential GSH transporter in the brain and astrocytes (9,79). By contrast, some organelles, such as the nucleus, have their own GSH pools, which are independent of cytosolic GSH (88).…”

Section: Cellular Distribution Of the Gsh/gssg Couplementioning

confidence: 99%

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Metabolic Responses to Reductive Stress

Xiao

Loscalzo

2020

Antioxidants & Redox Signaling

253

187

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Significance: Reducing equivalents (NAD(P)H and glutathione [GSH]) are essential for maintaining cellular redox homeostasis and for modulating cellular metabolism. Reductive stress induced by excessive levels of reduced NAD + (NADH), reduced NADP + (NADPH), and GSH is as harmful as oxidative stress and is implicated in many pathological processes. Recent Advances: Reductive stress broadens our view of the importance of cellular redox homeostasis and the influences of an imbalanced redox niche on biological functions, including cell metabolism. Critical Issues: The distribution of cellular NAD(H), NADP(H), and GSH/GSH disulfide is highly compartmentalized. Understanding how cells coordinate different pools of redox couples under unstressed and stressed conditions is critical for a comprehensive view of redox homeostasis and stress. It is also critical to explore the underlying mechanisms of reductive stress and its biological consequences, including effects on energy metabolism. Future Directions: Future studies are needed to investigate how reductive stress affects cell metabolism and how cells adapt their metabolism to reductive stress. Whether or not NADH shuttles and mitochondrial nicotinamide nucleotide transhydrogenase enzyme can regulate hypoxia-induced reductive stress is also a worthy pursuit. Developing strategies (e.g., antireductant approaches) to counteract reductive stress and its related adverse biological consequences also requires extensive future efforts. Antioxid. Redox Signal. 32, 1330-1347.

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Section: Cellular Distribution Of the Gsh/gssg Couplementioning

confidence: 95%

Section: Cellular Distribution Of the Gsh/gssg Couplementioning

confidence: 99%

Metabolic Responses to Reductive Stress

Xiao

Loscalzo

2020

Antioxidants & Redox Signaling

253

187

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“…Experiments with rxYFP and roGFP-based sensors indicate that the matrix glutathione pool is highly reduced, E GSH < −300 mV, similar to the cytosol (Calabrese et al 2017;Hanson et al 2004;Hu et al 2008;Kojer et al 2012;Morgan et al 2011). However, irrespective of the identity of the glutathione transporters in the IMM, it appears that the transport of glutathione across the IMM is very slow.…”

Section: The Matrix Glutathione Pool Appears To Be Kinetically Isolatmentioning

confidence: 99%

Glutathione: subcellular distribution and membrane transport

Oestreicher

Morgan

2019

Biochem. Cell Biol.

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Glutathione (γ-glutamylcysteinylglycine) is a small tripeptide found at millimolar concentrations in nearly all eukaryotes as well as many prokaryotic cells. Glutathione synthesis is restricted to the cytosol in animals and fungi and to the cytosol and plastids in plants. Nonetheless, glutathione is found in virtually all subcellular compartments. This implies that transporters must exist, which facilitate glutathione transport into and out of the various subcellular compartments. Glutathione may also be exported and imported across the plasma membrane in many cells. However, in most cases, the molecular identity of these transporters remains unclear. Whilst glutathione transport is essential for the supply and replenishment of subcellular glutathione pools, recent evidence supports a more active role for glutathione transport in the regulation of subcellular glutathione redox homeostasis. However, our knowledge of glutathione redox homeostasis at the level of specific subcellular compartments remains remarkably limited and the role of glutathione transport remains largely unclear. In this review we discuss how new tools and techniques have begun to yield insights into subcellular glutathione distribution and glutathione redox homeostasis. In particular, we discuss the known and putative glutathione transporters and examine their contribution to the regulation of subcellular glutathione redox homeostasis.

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“…It is well known that intracellular GSH works as a free radical scavenger, which protects cells against ROS, and that the accumulation of proteins with irreversible thiol oxidation is a parameter of ROS-induced cellular damage (Kettenhofen & Wood, 2010). It was reported that the mitochondrial sulfhydryl group was also a critical target site for chemical compounds in rat hepatocytes (Calabrese, Morgan, & Riemer, 2017;Chernyak & Bernardi, 1996;Nakagawa et al, 2014). Previous studies showed that the oxidation of GSH to GSSG caused the formation of mixed disulfides between GSSG and cellular protein thiols and that a factor in their formation is related to the concentration of intracellular GSSG (Fawthrop, Boobis, & Davies, 1991;Nakagawa, Moldéus, & Cotgreave, 1992;Reed, 1990), suggesting that a slight loss of protein thiols caused by DETX may be dependent on the formation of mixed disulfides ( Figure 4).…”

Section: Comparative Cytotoxic Effects Of Xanthone and Thioxanthonementioning

confidence: 99%

“…Previous studies showed that the oxidation of GSH to GSSG caused the formation of mixed disulfides between GSSG and cellular protein thiols and that a factor in their formation is related to the concentration of intracellular GSSG (Fawthrop, Boobis, & Davies, 1991;Nakagawa, Moldéus, & Cotgreave, 1992;Reed, 1990), suggesting that a slight loss of protein thiols caused by DETX may be dependent on the formation of mixed disulfides ( Figure 4). It was reported that the mitochondrial sulfhydryl group was also a critical target site for chemical compounds in rat hepatocytes (Calabrese, Morgan, & Riemer, 2017;Chernyak & Bernardi, 1996;Nakagawa et al, 2014).…”

Section: Comparative Cytotoxic Effects Of Xanthone and Thioxanthonementioning

confidence: 99%

Cytotoxic effects of thioxanthone derivatives as photoinitiators on isolated rat hepatocytes

Nakagawa

Inomata

Moriyasu

et al. 2019

J of Applied Toxicology

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Thioxanthone and its analogues, 2-or 4-isopropylthioxanthone, 2-chlorothioxanthone, 2,4-diethylthioxanthone (DETX) and xanthone, are used as photoinitiators of ultraviolet (UV) light-initiated curable inks. As these photoinitiators were found in numerous food/beverage products packaged in cartons printed with UV-cured inks, the cytotoxic effects and mechanisms of these compounds were studied in freshly isolated rat hepatocytes. The toxicity of DETX was greater than that of other compounds. DETX elicited not only concentration (0-2.0 mM)-and time (0-3 hours)-dependent cell death accompanied by the depletion of cellular adenosine triphosphate (ATP), and reduced glutathione (GSH) and protein thiol levels, but also the accumulation of GSH disulfide and malondialdehyde. Pretreatment of hepatocytes with either fructose at a concentration of 10 mM or N-acet yl-L-cysteine (NAC) at a concentration of 5.0 mM ameliorated DETX (1 mM)-induced cytotoxicity. Further, the exposure of hepatocytes to DETX resulted in the induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential, both of which were partially prevented by the addition of NAC. These results indicate that: (1) DETX-induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were, at least in part, ameliorated by the addition of fructose; and (3) GSH loss and/or ROS formation was prevented by NAC. Taken collectively, these results suggest that the onset of toxic effects caused by DETX may be partially attributable to cellular energy stress as well as oxidative stress.The exposure of rat hepatocytes to thioxanthone photoinitiators, especially 2,4diethylthioxanthone (DETX), caused cell death accompanied by the depletion of intracellular ATP and glutathione, and the induction of glutathione disulfide, all of which were partially prevented by the preincubation with N-acetyl-L-cysteine (NAC) or fructose. DETXinduced cytotoxicity was also associated by mitochondrial dysfunction and reactive oxygen species formation, which could be prevented by NAC. These results suggest that DETXinduced cytotoxicity may be attributable to cellular energy stress and/or oxidative stress.

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Mitochondrial Glutathione: Regulation and Functions

Cited by 139 publications

References 137 publications

Metabolic Responses to Reductive Stress

Metabolic Responses to Reductive Stress

Glutathione: subcellular distribution and membrane transport

Cytotoxic effects of thioxanthone derivatives as photoinitiators on isolated rat hepatocytes

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