title: Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome.
abstract: Calorie restriction (CR) extends life span in diverse species. Mitochondria play a key role in CR adaptation; however, the molecular details remain elusive. We developed and applied a quantitative mass spectrometry method to probe the liver mitochondrial acetyl-proteome during CR versus control diet in mice that were wild-type or lacked the protein deacetylase SIRT3. Quantification of 3,285 acetylation sites-2,193 from mitochondrial proteins-rendered a comprehensive atlas of the acetyl-proteome and enabled global site-specific, relative acetyl occupancy measurements between all four experimental conditions. Bioinformatic and biochemical analyses provided additional support for the effects of specific acetylation on mitochondrial protein function. Our results (1) reveal widespread reprogramming of mitochondrial protein acetylation in response to CR and SIRT3, (2) identify three biochemically distinct classes of acetylation sites, and (3) provide evidence that SIRT3 is a prominent regulator in CR adaptation by coordinately deacetylating proteins involved in diverse pathways of metabolism and mitochondrial maintenance.
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Hebert
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Dittenhafer-Reed
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Bailey
authors.forename: Ebru Selin
authors.initials: ES
authors.lastname: Selen
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Boersma
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Carson
authors.forename: Marco
authors.initials: M
authors.lastname: Tonelli
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Balloon
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Higbee
authors.forename: Michael S
authors.initials: MS
authors.lastname: Westphall
authors.forename: David J
authors.initials: DJ
authors.lastname: Pagliarini
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.forename: Fariba
authors.initials: F
authors.lastname: Assadi-Porter
authors.forename: Sushmita
authors.initials: S
authors.lastname: Roy
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Coon
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000222:Adaptation, Physiological; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D050260:Carbohydrate Metabolism; D002478:Cells, Cultured; D002852:Chromatography, Ion Exchange; D016000:Cluster Analysis; D016384:Consensus Sequence; D015870:Gene Expression; D050259:Genes, Mitochondrial; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D056566:Sirtuin 3 / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D013194:Staining and Labeling; D053719:Tandem Mass Spectrometry
chemical_list: D000596:Amino Acids; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D020543:Proteome; C525046:Sirt3 protein, mouse; D000105:Acetyl Coenzyme A; D056566:Sirtuin 3