Mitochondrial protein acetylation in the failing heart


Collaborating Investigator/s

Daniel Kelly (Sanford-Burnham Medical Research Institute); Deborah Muoio (Duke University); Kenneth Marguiles (University of Pennsylvania); Kenneth Bedi (University of Pennsylvania)



Myocardial fuel and energy metabolic derangements contribute to the pathogenesis of heart failure. Recent evidence implicates post-translational 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 post-translational modification of mitochondrial proteins during the development of heart failure. We used myocardial acetyl-proteomic technologies to demonstrate extensive mitochondrial protein lysine hyper-acetylation 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.