Dataset Information

Disruption of acetyl group balance in cardiomyocytes augments the mitochondrial acetylproteome without affecting respiratory function or heart susceptibility to pressure overload

ABSTRACT: Circumstantial evidence links the development of heart failure to perturbations in oxidative metabolism and corresponding shifts in post-translational modifications (PTMs) of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that acetyl-PTMs compromise mitochondrial performance remains sparse. Here, we used a respiratory diagnostics platform and serial assessment of cardiac phenotype to evaluate functional consequences of mitochondrial hyperacetylation caused by cardiac deficiency of carnitine acetyltransferase (CrAT) and sirtuin 3 (Sirt3); enzymes that oppose Kac by buffering the acetyl CoA pool and catalyzing lysine deacetylation, respectively. Although the dual knockout (DKO) manipulation raised the cardiac acetyl-lysine landscape well beyond that observed in response to Sirt3 deficiency or pathophysiological heart remodeling, bioenergetics of DKO mitochondria were remarkably normal. Moreover, DKO hearts were not more vulnerable to pressure overload-induced dysfunction resulting from chronic transaortic constriction. The findings challenge the premise that hyperacetylation per se threatens metabolic resilience by causing broad-ranging damage to mitochondrial proteins. See Davidson et. al. 2019 for further experimental details, reagents, and references.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Michael Davidson

LAB HEAD: Deb Muoio

PROVIDER: PXD013935 | Pride | 2020-10-02

REPOSITORIES: Pride

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Publications

Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.

Davidson Michael T MT Grimsrud Paul A PA Lai Ling L Draper James A JA Fisher-Wellman Kelsey H KH Narowski Tara M TM Abraham Dennis M DM Koves Timothy R TR Kelly Daniel P DP Muoio Deborah M DM

Circulation research 20200714 8

<h4>Rationale</h4>Circumstantial evidence links the development of heart failure to posttranslational modifications of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that Kac compromises mitochondrial performance remains sparse.<h4>Objective</h4>This study sought to explore the premise that mitochondrial Kac contributes to heart failure by disrupting oxidative metabolism.<h4>Methods and results</h4>A DKO (dual knockout) mouse line with deficiencies in Cr ...[more]

PMID: 32660330

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Project description:The trimeric thrombospondin homologs, TSP1 and TSP2, are both components of bone tissue and contribute in redundant and distinct ways to skeletal physiology. The functional effects of combined TSP1 and TSP2 deficiency remain to be elucidated. Here, we examined the spectrum of detergent soluble proteins in diaphyseal cortical bone of growing (6-week old) male and female mice deficient in both thrombospondins (double knockout (DKO)). Equal amounts of detergent soluble cortical bone protein were subject to Tandem Mass Tags (TMT) quantitative proteomics. 3,429 proteins met the selection criteria (FDR≤ 1% and 2 peptide spectral matches). 181 proteins were differentially abundant in both male and female DKO bones (≥1.95 fold or ≤0.55 fold compared to wild-type). Physiologically relevant annotation terms identified by Ingenuity Pathway Analysis included “ECM degradation” and “Quantity of Monocytes.” Manual inspection revealed that a number of proteins with shared expression among osteoclasts and osteocytes were reduced in DKO bones. To associate changes in protein content with phenotype, we examined 12-week old male DKO and WT mice. DKO mice were smaller than WT. DKO femora had reduced cross-sectional area with a flattened, less circular cross-section. DKO bones were less stiff in bending, but this reduction was disproportionate to the decreases in bending moment of inertia on nanoCT leading to a modest increase in predicted modulus (stiffness/bending moment). DKO displayed a lower ultimate load along with increases in both ultimate displacement and yield displacement. The ratio of ultimate displacement to yield displacement was actually higher in DKO, suggesting that decreased yield displacement does not account entirely for the reduction in ultimate displacement. Together, these mechanical attributes suggest compensation for small bone size through mechanisms that are not explained by nanoCT structural analysis. DKO mice also exhibited reductions in trabecular bone mass, which were surprisingly associated with increased osteoblast numbers and osteoid surface. Marrow-derived colony forming unit-fibroblastic was reduced in DKO mice. Together our data suggest that when both TSP1 and TSP2 are absent, a unique bone phenotype not predicted by the single knockouts, is manifested

Dataset Information

Disruption of acetyl group balance in cardiomyocytes augments the mitochondrial acetylproteome without affecting respiratory function or heart susceptibility to pressure overload

Publications

Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.

Similar Datasets

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