title: A quantitative map of the liver mitochondrial phosphoproteome reveals posttranslational control of ketogenesis.
abstract: Mitochondria are dynamic organelles that play a central role in a diverse array of metabolic processes. Elucidating mitochondrial adaptations to changing metabolic demands and the pathogenic alterations that underlie metabolic disorders represent principal challenges in cell biology. Here, we performed multiplexed quantitative mass spectrometry-based proteomics to chart the remodeling of the mouse liver mitochondrial proteome and phosphoproteome during both acute and chronic physiological transformations in more than 50 mice. Our analyses reveal that reversible phosphorylation is widespread in mitochondria, and is a key mechanism for regulating ketogenesis during the onset of obesity and type 2 diabetes. Specifically, we have demonstrated that phosphorylation of a conserved serine on Hmgcs2 (S456) significantly enhances its catalytic activity in response to increased ketogenic demand. Collectively, our work describes the plasticity of this organelle at high resolution and provides a framework for investigating the roles of proteome restructuring and reversible phosphorylation in mitochondrial adaptation.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grimsrud
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Carson
authors.forename: Alex S
authors.initials: AS
authors.lastname: Hebert
authors.forename: Shane L
authors.initials: SL
authors.lastname: Hubler
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Niemi
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Bailey
authors.forename: Adam
authors.initials: A
authors.lastname: Jochem
authors.forename: Donald S
authors.initials: DS
authors.lastname: Stapleton
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.forename: Michael S
authors.initials: MS
authors.lastname: Westphall
authors.forename: Brian S
authors.initials: BS
authors.lastname: Yandell
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Coon
authors.forename: David J
authors.initials: DJ
authors.lastname: Pagliarini
mesh_terms: D000818:Animals; D016208:Databases, Factual; D057809:HEK293 Cells; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D008930:Mitochondria, Liver / Q000378:metabolism*; D010748:Phosphopeptides / Q000032:analysis; D010766:Phosphorylation; D020543:Proteome / Q000032:analysis*; D040901:Proteomics; D053719:Tandem Mass Spectrometry
chemical_list: D007657:Ketone Bodies; D010748:Phosphopeptides; D020543:Proteome; D006904:Hydroxymethylglutaryl-CoA Synthase