title: SIRT3 deficiency impairs mitochondrial and contractile function in the heart.
abstract: Sirtuin 3 (SIRT3) is a mitochondrial NAD(+)-dependent deacetylase that regulates energy metabolic enzymes by reversible protein lysine acetylation in various extracardiac tissues. The role of SIRT3 in myocardial energetics and in the development of mitochondrial dysfunction in cardiac pathologies, such as the failing heart, remains to be elucidated. To investigate the role of SIRT3 in the regulation of myocardial energetics and function SIRT3(-/-) mice developed progressive age-related deterioration of cardiac function, as evidenced by a decrease in ejection fraction and an increase in enddiastolic volume at 24 but not 8 weeks of age using echocardiography. Four weeks following transverse aortic constriction, ejection fraction was further decreased in SIRT3(-/-) mice compared to WT mice, accompanied by a greater degree of cardiac hypertrophy and fibrosis. In isolated working hearts, a decrease in cardiac function in SIRT3(-/-) mice was accompanied by a decrease in palmitate oxidation, glucose oxidation, and oxygen consumption, whereas rates of glycolysis were increased. Respiratory capacity and ATP synthesis were decreased in cardiac mitochondria of SIRT3(-/-) mice. HPLC measurements revealed a decrease of the myocardial ATP/AMP ratio and of myocardial energy charge. Using LC-MS/MS, we identified increased acetylation of 84 mitochondrial proteins, including 6 enzymes of fatty acid import and oxidation, 50 subunits of the electron transport chain, and 3 enzymes of the tricarboxylic acid cycle. Lack of SIRT3 impairs mitochondrial and contractile function in the heart, likely due to increased acetylation of various energy metabolic proteins and subsequent myocardial energy depletion.
authors.affiliation: Division of Cardiology and Angiology I, Heart Center Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Koentges
authors.forename: Katharina
authors.initials: K
authors.lastname: Pfeil
authors.forename: Tilman
authors.initials: T
authors.lastname: Schnick
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wiese
authors.forename: Rabea
authors.initials: R
authors.lastname: Dahlbock
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cimolai
authors.forename: Maximilian
authors.initials: M
authors.lastname: Meyer-Steenbuck
authors.forename: Katarina
authors.initials: K
authors.lastname: Cenkerova
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Jaeger
authors.forename: Katja E
authors.initials: KE
authors.lastname: Odening
authors.forename: Bernd
authors.initials: B
authors.lastname: Kammerer
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle; D004734:Energy Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology*; D009200:Myocardial Contraction; D010085:Oxidative Phosphorylation; D056566:Sirtuin 3 / Q000502:physiology*
chemical_list: C525046:Sirt3 protein, mouse; D056566:Sirtuin 3