title: c-Myc and AMPK Control Cellular Energy Levels by Cooperatively Regulating Mitochondrial Structure and Function.
abstract: The c-Myc (Myc) oncoprotein and AMP-activated protein kinase (AMPK) regulate glycolysis and oxidative phosphorylation (Oxphos) although often for different purposes. Because Myc over-expression depletes ATP with the resultant activation of AMPK, we explored the potential co-dependency of and cross-talk between these proteins by comparing the consequences of acute Myc induction in ampk+/+ (WT) and ampk-/- (KO) murine embryo fibroblasts (MEFs). KO MEFs showed a higher basal rate of glycolysis than WT MEFs and an appropriate increase in response to activation of a Myc-estrogen receptor (MycER) fusion protein. However, KO MEFs had a diminished ability to increase Oxphos, mitochondrial mass and reactive oxygen species in response to MycER activation. Other differences between WT and KO MEFs, either in the basal state or following MycER induction, included abnormalities in electron transport chain function, levels of TCA cycle-related oxidoreductases and cytoplasmic and mitochondrial redox states. Transcriptional profiling of pathways pertinent to glycolysis, Oxphos and mitochondrial structure and function also uncovered significant differences between WT and KO MEFs and their response to MycER activation. Finally, an unbiased mass-spectrometry (MS)-based survey capable of quantifying ~40% of all mitochondrial proteins, showed about 15% of them to be AMPK- and/or Myc-dependent in their steady state. Significant differences in the activities of the rate-limiting enzymes pyruvate kinase and pyruvate dehydrogenase, which dictate pyruvate and acetyl coenzyme A abundance, were also differentially responsive to Myc and AMPK and could account for some of the differences in basal metabolite levels that were also detected by MS. Thus, Myc and AMPK are highly co-dependent and appear to engage in significant cross-talk across numerous pathways which support metabolic and ATP-generating functions.
authors.affiliation: Section of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States of America; The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
authors.forename: Lia R
authors.initials: LR
authors.lastname: Edmunds
authors.affiliation: Section of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States of America.
authors.forename: Lokendra
authors.initials: L
authors.lastname: Sharma
authors.affiliation: Section of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States of America.
authors.forename: Huabo
authors.initials: H
authors.lastname: Wang
authors.affiliation: The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
authors.forename: Audry
authors.initials: A
authors.lastname: Kang
authors.affiliation: Section of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States of America.
authors.forename: Sonia
authors.initials: S
authors.lastname: d'Souza
authors.affiliation: Section of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Dolezal
authors.affiliation: Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio TX, United States of America.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio TX, United States of America.
authors.forename: Susan T
authors.initials: ST
authors.lastname: Weintraub
authors.affiliation: Department of Biostatistics, The University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Cell Biology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Cell Biology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Yates
authors.affiliation: Section of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States of America; The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; The Hillman Cancer Center, The University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Prochownik
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D002461:Cell Line, Transformed; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D020543:Proteome; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*
chemical_list: C489428:Myc protein, mouse; D020543:Proteome; D016271:Proto-Oncogene Proteins c-myc; D000263:Adenylate Kinase