title: Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3.
abstract: 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 non-phosphorylating 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.
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada, K1H 8M5.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Mailloux
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.forename: Céline
authors.initials: C
authors.lastname: Aguer
authors.forename: Sheila
authors.initials: S
authors.lastname: Collins
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003545:Cysteine / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics*; D008954:Models, Biological; D032446:Myoblasts / Q000166:cytology; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; C000604393:Ucp3 protein, mouse; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D005978:Glutathione; D003545:Cysteine