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Disruption of acetyl-lysine turnover in muscle mitochondria promotes insulin resistance and redox stress without overt respiratory dysfunction

ABSTRACT: A double knockout (DKO) mouse model harboring muscle-specific deficits in acetyl CoA buffering by carnitine acetyltransferase (CrAT), and lysine deacetylation by SIRT3, resulted in additive hyperacetylation of the mitochondrial proteome, which was augmented exponentially by chronic high fat feeding. Whereas DKO mice developed a more severe form of diet-induced insulin resistance than either single KO mouse line, the functional profiles of hyperacetylated mitochondria were largely negative. Of the >120 measures of respiratory kinetics and thermodynamics assayed in DKO skeletal muscle mitochondria, the most consistently observed traits of a markedly heightened acetyl-lysine landscape were enhanced oxygen flux in the context of a long chain fatty acid fuel, and elevated rates of complex I-dependent electron leak. In sum, the findings challenge the notion that lysine acetylation causes broad-ranging damage to mitochondrial quality and performance, and raise the possibility that acetyl-lysine turnover, rather than acetyl-lysine stoichiometry, modulates redox balance and carbon flux.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle

DISEASE(S): Obesity

SUBMITTER: Paul Grimsrud

LAB HEAD: Deborah M. Muoio

PROVIDER: PXD014586 | Pride | 2019-11-25

REPOSITORIES: Pride

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			Action	DRS
	2017-06-13_S3vDKOSkm_TMT10_Acetyl_PAG_20170614_Run2_postinjection.raw	Raw
	2017-06-13_S3vDKOSkm_TMT10_Acetyl_PAG_20170614_Run3.raw	Raw
	2017-08-11_DKOvCrATskmTMT10_Acetyl-1.pep.xml	Pepxml
	2017-08-11_DKOvCrATskmTMT10_InputF1_PAG_20170803.raw	Raw
	2017-08-11_DKOvCrATskmTMT10_InputF2_PAG_20170803.raw	Raw

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Disruption of acetyl-lysine turnover in muscle mitochondria promotes insulin resistance and redox stress without overt respiratory dysfunction

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