Mitochondrial Thiols in Antioxidant Protection and Redox Signaling: Distinct Roles for Glutathionylation and Other Thiol Modifications

Murphy, Michael P.

doi:10.1089/ars.2011.4289

Cited by 300 publications

(266 citation statements)

References 225 publications

(379 reference statements)

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“…What remains elusive however is how Grx2 actually conjugates glutathione to UCP3 and how ROS subsequently remove this moiety. However, based on our findings and work published by others (41,44), it is increasingly clear that redox circuits govern important mitochondrial processes, including energetics, by eliciting their glutathionylation and deglutathionylation.…”

Section: Discussionsupporting

confidence: 65%

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Glutaredoxin-2 Is Required to Control Proton Leak through Uncoupling Protein-3

Mailloux

Xuan

Beauchamp

et al. 2013

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 65%

“…In fact, the increase in GPx4 in muscle mitochondria from Grx2 Ϫ/Ϫ mice was substantial. GPx4 is responsible for catalyzing the glutathione-mediated reduction of lipid hydroperoxides (44). Given our results, Grx2 Ϫ/Ϫ does alter glutathione homeostasis but not enough to induce oxidative damage in mitochondria from liver or muscle.…”

Section: Impact Of Grx2mentioning

confidence: 49%

Glutaredoxin-2 Is Required to Control Proton Leak through Uncoupling Protein-3

Mailloux

Xuan

Beauchamp

et al. 2013

Journal of Biological Chemistry

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“…Substrates for the reaction vary from hydrogen peroxide and smaller organic hydroperoxides to membranebound phospholipids and cholesterol hydroperoxides, in addition to other suitable thiol compounds (Sies, 1993). Many cellular proteins contain cysteine residues, are central to cellular homeostasis, and are sensitive to redox status (Murphy, 2012a). Thus, agents that block protein surface thiols can disrupt the activity of enzymes and transporters, by means of changing their redox status (Antony and Bayse, 2011).…”

Section: Introductionmentioning

confidence: 99%

Ebselen Alters Mitochondrial Physiology and Reduces Viability of Rat Hippocampal Astrocytes

Santofimia‐Castaño

Salido

González

2013

DNA and Cell Biology

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The seleno-organic compound and radical scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) have been extensively employed as an anti-inflammatory and neuroprotective compound. However, its glutathione peroxidase activity at the expense of cellular thiols groups could underlie certain deleterious actions of the compound on cell physiology. In this study, we have analyzed the effect of ebselen on rat hippocampal astrocytes in culture. Cellular viability, the intracellular free-Ca 2 + concentration ([Ca 2 + ] c ), the mitochondrial freeCa 2 + concentration ([Ca 2 + ] m ), and mitochondrial membrane potential (c m ) were analyzed. The caspase-3 activity was also assayed. Our results show that cell viability was reduced by treatment of cells with ebselen, depending on the concentration employed. In the presence of ebselen, we observed an initial transient increase in [Ca 2 + ] c that was then followed by a progressive increase to an elevated plateau. We also observed a transient increase in [Ca 2 + ] m in the presence of ebselen that returned toward a value over the prestimulation level. The compound induced depolarization of c m and altered the permeability of the mitochondrial membrane. Additionally, a disruption of the mitochondrial network was observed. Finally, we did not detect changes in caspase-3 activation in response to ebselen treatment. Collectively, these data support the likelihood of ebselen, depending on the concentration employed, reduces viability of rat hippocampal astrocytes via its action on the mitochondrial activity. These may be early effects that do not involve caspase-3 activation. We conclude that, depending on the concentration used, ebselen might exert deleterious actions on astrocyte physiology that could compromise cell function.

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“…The SH groups in the SSG, SNO and disulfide proteins can be reformed via various reactions involving GRX, TRX, TRXR and NADPH (Fig. 2B), allowing redox-dependent cell signaling events Nakamura and Lipton 2011;Murphy 2012;. There is a subtle balance between the production and removal of the different ROS molecules to maintain their intracellular concentration at a physiological level.…”

Section: Intracellular Ros Metabolismmentioning

confidence: 99%

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

Sieprath

Corne

Willems

et al. 2016

Advances in Anatomy, Embryology and Cell Biology

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Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and their removal by cellular antioxidant systems. Especially under pathological conditions, mitochondria constitute a relevant source of cellular ROS. These organelles harbor the electron transport chain, bringing electrons in close vicinity to molecular oxygen. Although a full understanding is still lacking, intracellular ROS generation and mitochondrial function are also linked to changes in mitochondrial morphology. To study the intricate relationships between the different factors that govern cellular redox balance in living cells, we have developed a high-content microscopy-based strategy for simultaneous quantification of intracellular ROS levels and mitochondrial morphofunction. Here, we summarize the principles of intracellular ROS generation and removal, and we explain the major considerations for performing quantitative microscopy analyses of ROS and mitochondrial morphofunction in living cells. Next, we describe our workflow and finally, we illustrate that a multiparametric readout enables the unambiguous classification of chemically perturbed cells as well as laminopathy patient cells. Principles of intracellular ROS generation and removalReactive oxygen species (ROS) are small, short-lived derivatives of molecular oxygen (O 2 ) of radical and non-radical nature (Halliwell and Gutteridge 2007 • ), nitrate radical (NO 3 • ) and many other nitrogen derivatives. ROS were originally described as molecular constituents of the defense system of phagocytic cells, but it has become clear that besides their damaging properties, they also function as signaling molecules and mediate a variety of other cellular responses including cell proliferation, differentiation, gene expression and migration (Lambeth 2004;Bartz and Piantadosi 2010). Intracellular ROS metabolismROS can be generated at various sites in the cell (Fig. 1A). This can be either deliberately, e.g. by NADPH oxidases (NOX), or as a byproduct, e.g. during normal cellular respiration in mitochondria (Babior 1999;Turrens 2003;Murphy 2009). The NOX family of NADPH oxidases (NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2) are proteins that transport electrons (e -) from NADPH across biological membranes (plasma or endomembranes) (Bedard and Krause 2007;Dupre-Crochet et al. 2013). The activation mechanisms and tissue distribution of the isoforms differ but they all use O 2 as e --acceptor, producing O 2•-. Through ROS generation, they play a role in many cellular processes including host defense, regulation of gene expression and cell differentiation (Bedard and Krause 2007). Despite their sometimes significant contribution to the global ROS pools, NOX are not the predominant source of intracellular ROS. Mitochondria are considered the major culprit, in particular under pathological conditions. Mitochondrial ROS are generated as a byproduct of the oxidative phosphorylation (OXPHOS, cf. below). Irrespective of its source, ROS production generally sta...

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Mitochondrial Thiols in Antioxidant Protection and Redox Signaling: Distinct Roles for Glutathionylation and Other Thiol Modifications

Abstract: Recent technical progress in the identification and quantification of thiol modifications by redox proteomics means that many of the questions raised about the multiple roles of mitochondrial thiols can now be addressed.

Cited by 300 publications

References 225 publications

Glutaredoxin-2 Is Required to Control Proton Leak through Uncoupling Protein-3

Glutaredoxin-2 Is Required to Control Proton Leak through Uncoupling Protein-3

Ebselen Alters Mitochondrial Physiology and Reduces Viability of Rat Hippocampal Astrocytes

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

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