Glutaredoxin-2 and Sirtuin-3 deficiencies impair cardiac mitochondrial energetics but their effects are not additive

Neoma T Boardman; Baher Migally; Chantal Pileggi; Gaganvir S Parmar; Jian Ying Xuan; Keir Menzies; Mary-Ellen Harper

doi:10.1016/j.bbadis.2020.165982

Glutaredoxin-2 and Sirtuin-3 deficiencies impair cardiac mitochondrial energetics but their effects are not additive

Biochim Biophys Acta Mol Basis Dis. 2021 Jan 1;1867(1):165982. doi: 10.1016/j.bbadis.2020.165982. Epub 2020 Sep 28.

Authors

Neoma T Boardman¹, Baher Migally², Chantal Pileggi², Gaganvir S Parmar², Jian Ying Xuan², Keir Menzies³, Mary-Ellen Harper⁴

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Department of Medical Biology, Faculty of Health Sciences, UiT-Arctic University of Norway, Tromsø, Norway.
² Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
³ Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada.
⁴ Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. Electronic address: mharper@uottawa.ca.

PMID: 33002579
DOI: 10.1016/j.bbadis.2020.165982

Abstract

Altered redox biology and oxidative stress have been implicated in the progression of heart failure. Glutaredoxin-2 (GRX2) is a glutathione-dependent oxidoreductase and catalyzes the reversible deglutathionylation of mitochondrial proteins. Sirtuin-3 (SIRT3) is a class III histone deacetylase and regulates lysine acetylation in mitochondria. Both GRX2 and SIRT3 are considered as key in the protection against oxidative damage in the myocardium. Knockout of either contributes to adverse heart pathologies including hypertrophy, hypertension, and cardiac dysfunction. Here, we created and characterized a GRX2 and SIRT3 double-knockout mouse model, hypothesizing that their deletions would have an additive effect on oxidative stress, and exacerbate mitochondrial function and myocardial structural remodeling. Wildtype, single-gene knockout (Sirt3^-/-, Grx2^-/-), and double-knockout mice (Grx2^-/-/Sirt3^-/-) were compared in heart weight, histology, mitochondrial respiration and H₂O₂ production. Overall, the hearts from Grx2^-/-/Sirt3^-/- mice displayed increased fibrosis and hypertrophy versus wildtype. In the Grx2^-/- and the Sirt3^-/- we observed changes in mitochondrial oxidative capacity, however this was associated with elevated H₂O₂ emission only in the Sirt3^-/-. Similar changes were observed but not worsened in hearts from Grx2^-/-/Sirt3^-/- mice, suggesting that these changes were not additive. In human myocardium, using genetic and histopathological data from the human Genotype-Tissue Expression consortium, we confirmed that SIRT3 expression correlates inversely with heart pathology. Altogether, GRX2 and SIRT3 are important in the control of cardiac mitochondrial redox and oxidative processes, but their combined absence does not exacerbate effects, consistent with the overall conclusion that they function together in the complex redox and antioxidant systems in the heart.

Keywords: Fibrosis; Glutathione; Hypertrophy; Mitochondria; Oxidative phosphorylation; Oxidative stress; Reactive oxygen species; Redox.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Energy Metabolism*
Glutaredoxins / deficiency*
Heart Failure / genetics
Heart Failure / metabolism*
Heart Failure / pathology
Hydrogen Peroxide / metabolism*
Mice
Mice, Knockout
Mitochondria, Heart / metabolism*
Mitochondria, Heart / pathology
Myocardium / metabolism*
Myocardium / pathology
Sirtuin 3 / deficiency*

Substances

Glrx2 protein, mouse
Glutaredoxins
Sirt3 protein, mouse
Hydrogen Peroxide
Sirtuin 3

Grants and funding

FDN 143278 /CAPMC/ CIHR/Canada