title: Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions.
abstract: Glutaredoxin-2 (Grx2) modulates the activity of several mitochondrial proteins in cardiac tissue by catalyzing deglutathionylation reactions. However, it remains uncertain whether Grx2 is required to control mitochondrial ATP output in heart. Here, we report that Grx2 plays a vital role modulating mitochondrial energetics and heart physiology by mediating the deglutathionylation of mitochondrial proteins. Deletion of Grx2 (Grx2(-/-)) decreased ATP production by complex I-linked substrates to half that in wild type (WT) mitochondria. Decreased respiration was associated with increased complex I glutathionylation diminishing its activity. Tissue glucose uptake was concomitantly increased. Mitochondrial ATP output and complex I activity could be recovered by restoring the redox environment to that favoring the deglutathionylated states of proteins. Grx2(-/-) hearts also developed left ventricular hypertrophy and fibrosis, and mice became hypertensive. Mitochondrial energetics from Grx2 heterozygotes (Grx2(+/-)) were also dysfunctional, and hearts were hypertrophic. Intriguingly, Grx2(+/-) mice were far less hypertensive than Grx2(-/-) mice. Thus, Grx2 plays a vital role in modulating mitochondrial metabolism in cardiac muscle, and Grx2 deficiency leads to pathology. As mitochondrial ATP production was restored by the addition of reductants, these findings may be relevant to novel redox-related therapies in cardiac disease.
authors.affiliation: From the Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Mailloux
authors.affiliation: From the Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Jian Ying
authors.initials: JY
authors.lastname: Xuan
authors.affiliation: From the Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Skye
authors.initials: S
authors.lastname: McBride
authors.affiliation: From the Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Wael
authors.initials: W
authors.lastname: Maharsy
authors.affiliation: the University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Thorn
authors.affiliation: the Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa Hospital, Ottawa, Ontario K1H 8L6, Canada, and.
authors.forename: Chet E
authors.initials: CE
authors.lastname: Holterman
authors.affiliation: the Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa Hospital, Ottawa, Ontario K1H 8L6, Canada, and.
authors.forename: Christopher R J
authors.initials: CR
authors.lastname: Kennedy
authors.affiliation: the University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Rippstein
authors.affiliation: the University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: deKemp
authors.affiliation: the University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: da Silva
authors.affiliation: From the Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
authors.affiliation: the Center of Redox Biology and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska at Lincoln, Lincoln, Nebraska 68583-0903.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Lou
authors.affiliation: From the Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, mharper@uottawa.ca.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D042967:Electron Transport Complex I / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000235:genetics; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation
chemical_list: C516009:Glrx2 protein, mouse; D054477:Glutaredoxins; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D005978:Glutathione
keywords: Bioenergetics; Cardiac Hypertrophy; Cardiac Metabolism; Glutaredoxin-2; Glutathione; Glutathionylation; Mitochondria; Oxidative Phosphorylation; Redox
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