title: Prolonged fasting identifies heat shock protein 10 as a Sirtuin 3 substrate: elucidating a new mechanism linking mitochondrial protein acetylation to fatty acid oxidation enzyme folding and function.
abstract: Although Sirtuin 3 (SIRT3), a mitochondrially enriched deacetylase and activator of fat oxidation, is down-regulated in response to high fat feeding, the rate of fatty acid oxidation and mitochondrial protein acetylation are invariably enhanced in this dietary milieu. These paradoxical data implicate that additional acetylation modification-dependent levels of regulation may be operational under nutrient excess conditions. Because the heat shock protein (Hsp) Hsp10-Hsp60 chaperone complex mediates folding of the fatty acid oxidation enzyme medium-chain acyl-CoA dehydrogenase, we tested whether acetylation-dependent mitochondrial protein folding contributes to this regulatory discrepancy. We demonstrate that Hsp10 is a functional SIRT3 substrate and that, in response to prolonged fasting, SIRT3 levels modulate mitochondrial protein folding. Acetyl mutagenesis of Hsp10 lysine 56 alters Hsp10-Hsp60 binding, conformation, and protein folding. Consistent with Hsp10-Hsp60 regulation of fatty acid oxidation enzyme integrity, medium-chain acyl-CoA dehydrogenase activity and fat oxidation are elevated by Hsp10 acetylation. These data identify acetyl modification of Hsp10 as a nutrient-sensing regulatory node controlling mitochondrial protein folding and metabolic function.
authors.affiliation: From the Cardiovascular and Pulmonary Branch and the Department of Biochemistry and Molecular Medicine, George Washington University, Washington, D. C. 20052, and the Veterans Affairs Medical Center, Washington, D. C. 20422 luz@gwu.edu.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Proteomic Core Facility, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Proteomic Core Facility, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Angel M
authors.initials: AM
authors.lastname: Aponte
authors.affiliation: the Department of Biochemistry and Molecular Medicine, George Washington University, Washington, D. C. 20052, and the Veterans Affairs Medical Center, Washington, D. C. 20422.
authors.forename: Valentina
authors.initials: V
authors.lastname: Battaglia
authors.affiliation: Proteomic Core Facility, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Marjan
authors.initials: M
authors.lastname: Gucek
authors.affiliation: From the Cardiovascular and Pulmonary Branch and sackm@nih.gov.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
mesh_terms: D000107:Acetylation; D000818:Animals; D018835:Chaperonin 10 / Q000235:genetics / Q000378:metabolism*; D002850:Chromatography, Gel; D015180:Electrophoresis, Gel, Two-Dimensional; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018832:Molecular Chaperones; D016296:Mutagenesis; D010100:Oxygen / Q000378:metabolism; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism*
chemical_list: D018835:Chaperonin 10; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; D056566:Sirtuin 3; D010100:Oxygen
keywords: Fatty Acid Oxidation; Heat Shock Protein (HSP); Mitochondria; Protein Folding; SIRT3; Sirtuin