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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Dataset's files

Source:

			Action	DRS
	Exp1_DKOvsSirt3_Acetyl-1.raw	Raw
	Exp1_DKOvsSirt3_Acetyl-2.raw	Raw
	Exp1_DKOvsSirt3_Acetyl-3.raw	Raw
	Exp1_DKOvsSirt3_Input-1.raw	Raw
	Exp1_DKOvsSirt3_Input-2.raw	Raw

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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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