Mitochondrial Complex II in the Post-ischemic Heart

Chen, Yeong Renn; Chen, Chwen Lih; Pfeiffer, Douglas R.; Zweíer, Jay L.

doi:10.1074/jbc.m702294200

Cited by 215 publications

(121 citation statements)

References 66 publications

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“…In addition, chronic exposure to very low amounts of menadione (5 and 10 M) was required to activate UCP3. A few proteins have been shown to be deglutathionylated when ROS levels increase; these include monomeric actin and SDH (43,44). Hence, although ROS is most often associated with increased glutathionylation, it is now more apparent that under certain circumstances, ROS also induce the deglutathionylation of proteins.…”

Section: Discussionmentioning

confidence: 99%

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

Mailloux

Seifert

Bouillaud

et al. 2011

Journal of Biological Chemistry

159

149

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The mitochondrial uncoupling proteins 2 and 3 (UCP2 and -3) are known to curtail oxidative stress and participate in a wide array of cellular functions, including insulin secretion and the regulation of satiety. However, the molecular control mechanism(s) governing these proteins remains elusive. Here we reveal that UCP2 and UCP3 contain reactive cysteine residues that can be conjugated to glutathione. We further demonstrate that this modification controls UCP2 and UCP3 function. Both reactive oxygen species and glutathionylation were found to activate and deactivate UCP3-dependent increases in nonphosphorylating respiration. We identified both Cys 25 and Cys 259 as the major glutathionylation sites on UCP3. Additional experiments in thymocytes from wild-type and UCP2 null mice demonstrated that glutathionylation similarly diminishes non-phosphorylating respiration. Our results illustrate that UCP2-and UCP3-mediated state 4 respiration is controlled by reversible glutathionylation. Altogether, these findings advance our understanding of the roles UCP2 and UCP3 play in modulating metabolic efficiency, cell signaling, and oxidative stress processes.UCP2 and -3 belong to the mitochondrial anion carrier family and are ϳ73% homologous to each other, and they are both ϳ58% homologous to the highly thermogenic uncoupling protein, UCP1. Whereas UCP3 is expressed in skeletal muscle and brown adipose tissue (BAT) 3 and to some extent in the heart, UCP2 is found in a wide variety of tissues (1). UCP2 and UCP3 have been shown to diminish oxidative stress by lowering the mitochondrial membrane potential (2, 3). Acute increases in reactive oxygen species (ROS) production increase proton conductance through both UCP2 and UCP3, providing a negative feedback loop to limit further mitochondrial ROS formation (4, 5). Furthermore, UCP2 and UCP3 have also been implicated in many physiologic functions, suggesting that the common underlying mechanism may be ROS-mediated cell signaling.Previous work has reported that UCP3 protects against insulin resistance and obesity (6 -9), whereas UCP2 has been implicated a broad range of functions, including hormone secretion from the pancreas, immune cell function, and feeding behavior (10 -13). For UCP2, most of these functions are linked to ROS level buffering (14 -16). Indeed, UCP2 null mice on various genetic backgrounds exhibit oxidative stress in many tissue types and a decrease in the circulating glutathione (GSH)/glutathione disulfide ratio (2, 12). Increased expression of UCP2 in cancer cells is associated with the acquisition of drug-resistant phenotypes, a phenomenon related to the ROS-quenching function of UCP2 (17, 18). The absence of UCP3 in skeletal muscle increases oxidative damage and perturbs skeletal muscle metabolism (19). Increased UCP3 expression in muscle augments fatty acid metabolism and also curtails ROS production during fatty acid oxidation (20,21). Remarkably, although they have been linked to a plethora of cellular processes, the molecular control of UCP2 and UCP3 ha...

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Section: Discussionmentioning

confidence: 99%

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

Mailloux

Seifert

Bouillaud

et al. 2011

Journal of Biological Chemistry

159

149

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“…In most cases, the detected S-glutathionylation of the complex was induced by GSSG (4,12) or by oxidative stress in vitro (5,11). Intrinsic S-glutathionylation has been detected in the isolated mitochondrial Complex II (8). However, intrinsic S-glutathionylation has not been detected in the isolated Complex I; presumably GS binding was progressively dissociated from Complex I during purification.…”

Section: Protein S-glutathionylation Of Complex I-protein S-glutathiomentioning

confidence: 97%

“…In Vivo Myocardial Regional Ischemia/Reperfusion ModelThe procedure for the in vivo ischemia-reperfusion rat model was performed by the technique reported in the literature (8,22,23). Sprague-Dawley rats (ϳ300 -350 g) were anesthetized with Nembutal administered intraperitoneally (80 -100 mg/kg).…”

mentioning

confidence: 99%

Peptide-based Antibodies against Glutathione-binding Domains Suppress Superoxide Production Mediated by Mitochondrial Complex I

Chen

Rawale

et al. 2010

Journal of Biological Chemistry

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-derived oxidants increases the ratio of GSSG 3 to GSH. Moreover, the proteins of the mitochondrial electron transport chain are rich in protein thiols (2, 3). It has been documented that Complex I is the major component of the electron transport chain to host protein thiols, which comprise structural thiols involved in the ligands of iron-sulfur clusters and the reactive/regulatory thiols that are thought to function in antioxidant defense and redox signaling (4, 5). Physiologically, the Complex I-derived regulatory thiols have been implicated in the regulation of respiration, nitric oxide utilization (6, 7), and redox status of mitochondria (1-3). It has been well documented that the 51-and 75-kDa subunits of the NQR hydrophilic domain are two of the major polypeptides that host regulatory thiols in mitochondria (4,5,12).We have reported previously that in oxidative damage to NQR, the C 206 moiety of the 51-kDa subunit plays a unique role as a reactive thiol, based on the evidence of immunospin trapping with 5,5-dimethyl pyrroline N-oxide and mass spectrometry (9). With a proteomic approach, we further determined that the Cys 206 of the 51-kDa subunit is involved in sitespecific S-glutathionylation (12). The peptide identified as 5,5-dimethyl pyrroline N-oxide-binding and GS binding is 200 GAGAYIC 206 GEETALIESIEGK 219 , which is highly conserved in the bacterial, fungal, and mammalian enzymes (90% sequence identity in the bacterial enzyme). An x-ray crystal structure of the hydrophilic domain of respiratory Complex I from Thermus thermophilus indicates that this conserved cysteine (Cys 182 in T. thermophilus) is only 6 Å from the FMN, * This work was supported, in whole or in part, by National Institutes of Health Grants HL83237 (to Y.-R. C.) and HL63744 (to J. L. Z.

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“…However, in the presence of succinate the GSH content was 40% higher. A partial protective effect of succinate against lipid peroxidation of RLM had been reported (Tretter et al 1987); however this paradoxical result was probably a consequence of GSH production by the deglutathionylation of SQR-SSG (glutathionylated succinate coenzyme Q reductase) that has been associated with superoxide ion production in mitochondria (Chen et al 2007). The Mn III TMPyP-promoted decreasing of the DMPO-OH signal was also associated with GSH depletion.…”

Section: Tmpyp Abolishes Ion Superoxide Epr Signal At Expenses Ofmentioning

confidence: 98%

Towards the mechanisms involved in the antioxidant action of MnIII [meso-tetrakis(4-N-methyl pyridinium) porphyrin] in mitochondria

Araújo-Chaves

Yokomizo

Kawai

et al. 2011

J Bioenerg Biomembr

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Aerobic organisms are afforded with an antioxidant enzymatic apparatus that more recently has been recognized to include cytochrome c, as it is able to prevent hydrogen peroxide generation by returning electrons from the superoxide ion back to the respiratory chain. The present study investigated the glutathione peroxidase (GPx), superoxide dismutase (SOD) and cytochrome c-like antioxidant activities of para Mn(III)TMPyP in isolated rat liver mitochondria (RLM) and mitoplasts. In RLM, Mn TMPyP is expected to be produced at the expense of NADPH/GSH oxidation. The present results suggest GPx-like activity to be the principal antioxidant mechanism of Mn III TMPyP, whose efficiency is dependent on the NADPH/GSH content in cells.

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Mitochondrial Complex II in the Post-ischemic Heart

Cited by 215 publications

References 66 publications

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

Peptide-based Antibodies against Glutathione-binding Domains Suppress Superoxide Production Mediated by Mitochondrial Complex I

Towards the mechanisms involved in the antioxidant action of MnIII [meso-tetrakis(4-N-methyl pyridinium) porphyrin] in mitochondria

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