title: SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells.
abstract: Pyruvate dehydrogenase E1α (PDHA1) is the first component enzyme of the pyruvate dehydrogenase (PDH) complex that transforms pyruvate, via pyruvate decarboxylation, into acetyl-CoA that is subsequently used by both the citric acid cycle and oxidative phosphorylation to generate ATP. As such, PDH links glycolysis and oxidative phosphorylation in normal as well as cancer cells. Herein we report that SIRT3 interacts with PDHA1 and directs its enzymatic activity via changes in protein acetylation. SIRT3 deacetylates PDHA1 lysine 321 (K321), and a PDHA1 mutant mimicking a deacetylated lysine (PDHA1(K321R)) increases PDH activity, compared to the K321 acetylation mimic (PDHA1(K321Q)) or wild-type PDHA1. Finally, PDHA1(K321Q) exhibited a more transformed in vitro cellular phenotype compared to PDHA1(K321R). These results suggest that the acetylation of PDHA1 provides another layer of enzymatic regulation, in addition to phosphorylation, involving a reversible acetyllysine, suggesting that the acetylome, as well as the kinome, links glycolysis to respiration.
authors.affiliation: Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Ozkan
authors.initials: O
authors.lastname: Ozden
authors.affiliation: Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, Free Radical and Radiation Biology, The University of Iowa, Iowa City, IA 52242.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.affiliation: Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Ha Yong
authors.initials: HY
authors.lastname: Song
authors.affiliation: Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL 60612.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jung
authors.affiliation: Department of Radiation Oncology, Free Radical and Radiation Biology, The University of Iowa, Iowa City, IA 52242.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.affiliation: Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: David
authors.initials: D
authors.lastname: Gius
mesh_terms: D000107:Acetylation; D015153:Blotting, Western; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D047468:Immunoprecipitation; D019344:Lactic Acid / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D017382:Reactive Oxygen Species; D019344:Lactic Acid; D019289:Pyruvic Acid; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D005947:Glucose; D008239:Lysine
keywords: Acetylation; Carcinogenesis; Free radicals; PDHA1; Pyruvate dehydrogenase; SIRT3; Warburg