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

Mailloux, Ryan J.; Xuan, Jian Ying; Beauchamp, Brittany; Jui, Linda; Lou, Marjorie F.; Harper, Mary‐Ellen

doi:10.1074/jbc.m112.442905

Cited by 62 publications

(93 citation statements)

References 65 publications

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“…Previous studies have indicated that Grx2 is a key regulator of redox homeostasis in the mitochondria, and it controls complex I activity in the electron transport system (ETS) for oxygen reduction and ATP production (37,38). The results in this study as shown in Figs.…”

Section: Discussionsupporting

confidence: 68%

Glutaredoxin 2 (Grx2) Gene Deletion Induces Early Onset of Age-dependent Cataracts in Mice

David

et al. 2014

Journal of Biological Chemistry

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Background:Mitochondrial glutaredoxin 2 is a member of the oxidoreductase family with disulfide reductase activity that repairs thiol oxidation-damaged proteins. Results: Glutaredoxin 2 null mice develop early cataracts during aging. Conclusion: Glutaredoxin 2 deletion causes mitochondrial malfunction and cataract formation and is a good model for studying the mechanism of human age-related cataracts. Significance: Thiol oxidation repair system is essential for lens transparency.

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Section: Discussionsupporting

confidence: 68%

Glutaredoxin 2 (Grx2) Gene Deletion Induces Early Onset of Age-dependent Cataracts in Mice

David

et al. 2014

Journal of Biological Chemistry

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“…Moreover, the AOX, uncoupling protein (UCP), and several peptides associated with the mitochondrial electron transport chain, alongside Gly decarboxylase, Ser hydroxymethyltransferase, several amino transferases, and enzymes of branched chain amino acid metabolism, were also identified as putative targets (13,19,22). Notably, in nonplant systems, other enzymes associated with the mitochondrial electron transport chain (e.g., complex II, UCP) have been identified as being redox-regulated (48,49). Here, we adopted .…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin, a master regulator of the tricarboxylic acid cycle in plant mitochondria

Daloso

Müller

Obata

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

192

186

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Plant mitochondria have a fully operational tricarboxylic acid (TCA) cycle that plays a central role in generating ATP and providing carbon skeletons for a range of biosynthetic processes in both heterotrophic and photosynthetic tissues. The cycle enzymeencoding genes have been well characterized in terms of transcriptional and effector-mediated regulation and have also been subjected to reverse genetic analysis. However, despite this wealth of attention, a central question remains unanswered: "What regulates flux through this pathway in vivo?" Previous proteomic experiments with Arabidopsis discussed below have revealed that a number of mitochondrial enzymes, including members of the TCA cycle and affiliated pathways, harbor thioredoxin (TRX)-binding sites and are potentially redox-regulated. We have followed up on this possibility and found TRX to be a redox-sensitive mediator of TCA cycle flux. In this investigation, we first characterized, at the enzyme and metabolite levels, mutants of the mitochondrial TRX pathway in Arabidopsis: the NADP-TRX reductase a and b double mutant (ntra ntrb) and the mitochondrially located thioredoxin o1 (trxo1) mutant. These studies were followed by a comparative evaluation of the redistribution of isotopes when 13 Cglucose, 13 C-malate, or 13 C-pyruvate was provided as a substrate to leaves of mutant or WT plants. In a complementary approach, we evaluated the in vitro activities of a range of TCA cycle and associated enzymes under varying redox states. The combined dataset suggests that TRX may deactivate both mitochondrial succinate dehydrogenase and fumarase and activate the cytosolic ATP-citrate lyase in vivo, acting as a direct regulator of carbon flow through the TCA cycle and providing a mechanism for the coordination of cellular function.Arabidopsis | redox regulation | thioredoxin TCA cycle regulation | citric acid cycle regulation | ATP-citrate lyase A s in animals and aerobic microorganisms (1, 2), the tricarboxylic acid (TCA) cycle of plant mitochondria is composed of a set of eight enzymes that oxidize pyruvate and malate formed in the cytosol to CO 2 and NADH (3). The CO 2 is released and the NADH is oxidized by the electron transport chain for the generation of ATP. Recent years have witnessed major advances in our understanding of the cycle in plants, including its different modes of operation and properties of its constituent enzymes (4-6). We also now understand a great deal about the physiological role, kinetic features, and transcriptional and posttranslational regulation of enzymes participating in the cycle.In addition to these studies, experiments have focused on functional interactions taking place between mitochondria and the other organelle that generates energy in plant cells, namely, the chloroplast (7, 8). The results suggest that the two compartments are tightly linked by regulatory mechanisms acting at the levels of the gene and interorganellar metabolite transport (9-13). Further, a long-standing body of evidence indicates that the cycle is regul...

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“…S-glutathionylation of UCP3 was also discovered to be catalyzed by the enzyme GRX2 (Mailloux et al, 2013). In GRX2 knock out mice, UCP3 was less glutathionylated which resulted in increased state 4 respiration (Mailloux et al, 2013). UCP2 has also been found to be S-glutathionylated, which was shown to play a part in regulating glucose-stimulated insulin release (Mailloux et al, 2012a,b).…”

Section: Uncoupling Proteins-2 Andmentioning

confidence: 99%

“…S-glutathionylation of UCP3 causes a decrease in state 4 respiration in primary cells and skeletal muscle mitochondria . S-glutathionylation of UCP3 was also discovered to be catalyzed by the enzyme GRX2 (Mailloux et al, 2013). In GRX2 knock out mice, UCP3 was less glutathionylated which resulted in increased state 4 respiration (Mailloux et al, 2013).…”

Section: Uncoupling Proteins-2 Andmentioning

confidence: 99%

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

Kuksal

Chalker

Mailloux

2017

Biological Chemistry

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Abstract:The molecular oxygen (O 2 ) paradox was coined to describe its essential nature and toxicity. The latter characteristic of O 2 is associated with the formation of reactive oxygen species (ROS), which can damage structures vital for cellular function. Mammals are equipped with antioxidant systems to fend off the potentially damaging effects of ROS. However, under certain circumstances antioxidant systems can become overwhelmed leading to oxidative stress and damage. Over the past few decades, it has become evident that ROS, specifically H 2 O 2 , are integral signaling molecules complicating the previous logos that oxyradicals were unfortunate by-products of oxygen metabolism that indiscriminately damage cell structures. To avoid its potential toxicity whilst taking advantage of its signaling properties, it is vital for mitochondria to control ROS production and degradation. H 2 O 2 elimination pathways are well characterized in mitochondria. However, less is known about how H 2 O 2 production is controlled. The present review examines the importance of mitochondrial H 2 O 2 in controlling various cellular programs and emerging evidence for how production is regulated. Recently published studies showing how mitochondrial H 2 O 2 can be used as a secondary messenger will be discussed in detail. This will be followed with a description of how mitochondria use S-glutathionylation to control H 2 O 2 production.

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

Cited by 62 publications

References 65 publications

Glutaredoxin 2 (Grx2) Gene Deletion Induces Early Onset of Age-dependent Cataracts in Mice

Glutaredoxin 2 (Grx2) Gene Deletion Induces Early Onset of Age-dependent Cataracts in Mice

Thioredoxin, a master regulator of the tricarboxylic acid cycle in plant mitochondria

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

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