title: Mitochondrial protein hyperacetylation in the failing heart.
abstract: Myocardial fuel and energy metabolic derangements contribute to the pathogenesis of heart failure. Recent evidence implicates posttranslational mechanisms in the energy metabolic disturbances that contribute to the pathogenesis of heart failure. We hypothesized that accumulation of metabolite intermediates of fuel oxidation pathways drives posttranslational modifications of mitochondrial proteins during the development of heart failure. Myocardial acetylproteomics demonstrated extensive mitochondrial protein lysine hyperacetylation in the early stages of heart failure in well-defined mouse models and the in end-stage failing human heart. To determine the functional impact of increased mitochondrial protein acetylation, we focused on succinate dehydrogenase A (SDHA), a critical component of both the tricarboxylic acid (TCA) cycle and respiratory complex II. An acetyl-mimetic mutation targeting an SDHA lysine residue shown to be hyperacetylated in the failing human heart reduced catalytic function and reduced complex II-driven respiration. These results identify alterations in mitochondrial acetyl-CoA homeostasis as a potential driver of the development of energy metabolic derangements that contribute to heart failure.
authors.affiliation: Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Horton
authors.affiliation: Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Ola J
authors.initials: OJ
authors.lastname: Martin
authors.affiliation: Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.affiliation: Department of Chemistry, University of Wisconsin - Madison, Madison, Wisconsin, USA; Genome Center of Wisconsin, University of Wisconsin - Madison, Madison, Wisconsin, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Riley
authors.affiliation: Department of Chemistry, University of Wisconsin - Madison, Madison, Wisconsin, USA; Genome Center of Wisconsin, University of Wisconsin - Madison, Madison, Wisconsin, USA.
authors.forename: Alicia L
authors.initials: AL
authors.lastname: Richards
authors.affiliation: Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Rick B
authors.initials: RB
authors.lastname: Vega
authors.affiliation: Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.affiliation: Department of Biochemistry, University of Wisconsin - Madison, Madison, Wisconsin, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pagliarini
authors.affiliation: Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, North Carolina, USA.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.affiliation: Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Bedi
authors.affiliation: Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: Department of Chemistry, University of Wisconsin - Madison, Madison, Wisconsin, USA; Genome Center of Wisconsin, University of Wisconsin - Madison, Madison, Wisconsin, USA; Department of Biomolecular Chemistry, University of Wisconsin - Madison, Madison, Wisconsin, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Coon
authors.affiliation: Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly