title: A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation.
abstract: DNA transcription, replication, and repair are regulated by histone acetylation, a process that requires the generation of acetyl-coenzyme A (CoA). Here, we show that all the subunits of the mitochondrial pyruvate dehydrogenase complex (PDC) are also present and functional in the nucleus of mammalian cells. We found that knockdown of nuclear PDC in isolated functional nuclei decreased the de novo synthesis of acetyl-CoA and acetylation of core histones. Nuclear PDC levels increased in a cell-cycle-dependent manner and in response to serum, epidermal growth factor, or mitochondrial stress; this was accompanied by a corresponding decrease in mitochondrial PDC levels, suggesting a translocation from the mitochondria to the nucleus. Inhibition of nuclear PDC decreased acetylation of specific lysine residues on histones important for G1-S phase progression and expression of S phase markers. Dynamic translocation of mitochondrial PDC to the nucleus provides a pathway for nuclear acetyl-CoA synthesis required for histone acetylation and epigenetic regulation.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada. Electronic address: gopinath.sutendra@ludwig.ox.ac.uk.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Sutendra
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Kinnaird
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Dromparis
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Trevor H
authors.initials: TH
authors.lastname: Stenson
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: nanoFAB Fabrication and Characterization Facility, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.affiliation: nanoFAB Fabrication and Characterization Facility, University of Alberta, Edmonton, AB T6G 2B7, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Flaim
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada. Electronic address: em2@ualberta.ca.
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000105:Acetyl Coenzyme A / Q000096:biosynthesis*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D021381:Protein Transport; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*
chemical_list: D006657:Histones; D011768:Pyruvate Dehydrogenase Complex; D000105:Acetyl Coenzyme A