Glutaredoxin-2 Is Required to Control Oxidative Phosphorylation in Cardiac Muscle by Mediating Deglutathionylation Reactions

Authors

Mary-Ellen Harper, University of Ottawa Faculty of MedicineFollow
Ryan J. Mailloux, University of Ottawa Faculty of Medicine
Jian Ying Xuan, University of Ottawa Faculty of Medicine
Skye McBride, University of Ottawa Faculty of Medicine
Wael Maharsy, University of Ottawa Faculty of Medicine
Stephanie Thorn, University of Ottawa Heart Institute
Chet E. Holterman, Ottawa Hospital Research Institute
Christopher R.J. Kennedy, Ottawa Hospital Research Institute
Peter Rippstein, University of Ottawa Heart Institute
Robert deKemp, University of Ottawa Heart Institute
Jean da Silva, University of Ottawa Heart Institute
Mona Nemer, University of Ottawa Faculty of Medicine
Marjorie Lou, University of Nebraska–LincolnFollow

Document Type

Article

Date of this Version

2014

Citation

Journal of Biological Chemistry 289 (2014), pp. 14812-14828; doi: 10.1074/jbc.M114.550574

Comments

Copyright 2014, Used by permission.

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.