title: AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1.
abstract: Adenosine monophosphate (AMP)-activated protein kinase (AMPK) acts as a master regulator of cellular energy homeostasis by directly phosphorylating metabolic enzymes and nutrient transporters and by indirectly promoting the transactivation of nuclear genes involved in mitochondrial biogenesis and function. We explored the mechanism of AMPK-mediated induction of gene expression. We identified AMPK consensus phosphorylation sequences in three proteins involved in nucleosome remodeling: DNA methyltransferase 1 (DNMT1), retinoblastoma binding protein 7 (RBBP7), and histone acetyltransferase 1 (HAT1). DNMT1 mediates DNA methylation that limits transcription factor access to promoters and is inhibited by RBBP7. Acetylation of histones by HAT1 creates a more relaxed chromatin-DNA structure that favors transcription. AMPK-mediated phosphorylation resulted in the activation of HAT1 and inhibition of DNMT1. For DNMT1, this inhibition was both a direct effect of phosphorylation and the result of increased interaction with RBBP7. In human umbilical vein cells, pharmacological AMPK activation or pulsatile shear stress triggered nucleosome remodeling and decreased cytosine methylation, leading to increased expression of nuclear genes encoding factors involved in mitochondrial biogenesis and function, such as peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), transcription factor A (Tfam), and uncoupling proteins 2 and 3 (UCP2 and UCP3). Similar effects were seen in the aortas of mice given pharmacological AMPK activators, and these effects required AMPK2α. These results enhance our understanding of AMPK-mediated mitochondrial gene expression through nucleosome remodeling.
authors.affiliation: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA.|Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521, USA.|Department of Cardiopulmonary Sciences, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Traci L
authors.initials: TL
authors.lastname: Marin
authors.affiliation: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA.|Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521, USA.|Department of Cardiopulmonary Sciences, Loma Linda University, Loma Linda, CA 92350, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Gongol
authors.affiliation: Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA.|Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Marcy
authors.initials: M
authors.lastname: Martin
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Johnson
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Bioengineering, Cellular and Molecular Medicine, and Computer Science and Engineering, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.|Departments of Bioengineering, Cellular and Molecular Medicine, and Computer Science and Engineering, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA. jshyy@ucsd.edu.
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D056524:Retinoblastoma-Binding Protein 7 / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071246:Uncoupling Protein 2 / Q000235:genetics / Q000378:metabolism; D000071247:Uncoupling Protein 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D009707:Nucleosomes; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C490746:RBBP7 protein, human; D056524:Retinoblastoma-Binding Protein 7; C499631:TFAM protein, human; D014157:Transcription Factors; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D051548:Histone Acetyltransferases; C110880:histone acetyltransferase type B complex; D055372:AMP-Activated Protein Kinases