Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3.

Mailloux RJ, Seifert EL, Bouillaud F, Aguer C, Collins S, Harper ME
J Biol Chem. 2011 286 (24): 21865-75

PMID: 21515686 · PMCID: PMC3122241 · DOI:10.1074/jbc.M111.240242

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.

MeSH Terms (17)

Animals Cells, Cultured Cysteine Glutathione Ion Channels Mice Mice, Knockout Mice, Transgenic Mitochondrial Proteins Models, Biological Myoblasts Oxidative Stress Protein Processing, Post-Translational Reactive Oxygen Species Thymus Gland Uncoupling Protein 2 Uncoupling Protein 3

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