title: Metabolic plasticity maintains proliferation in pyruvate dehydrogenase deficient cells.
abstract: BACKGROUND
  Pyruvate dehydrogenase (PDH) occupies a central node of intermediary metabolism, converting pyruvate to acetyl-CoA, thus committing carbon derived from glucose to an aerobic fate rather than an anaerobic one. Rapidly proliferating tissues, including human tumors, use PDH to generate energy and macromolecular precursors. However, evidence supports the benefits of constraining maximal PDH activity under certain contexts, including hypoxia and oncogene-induced cell growth. Although PDH is one of the most widely studied enzyme complexes in mammals, its requirement for cell growth is unknown. In this study, we directly addressed whether PDH is required for mammalian cells to proliferate.
  
  
  RESULTS
  We genetically suppressed expression of the PDHA1 gene encoding an essential subunit of the PDH complex and characterized the effects on intermediary metabolism and cell proliferation using a combination of stable isotope tracing and growth assays. Surprisingly, rapidly dividing cells tolerated loss of PDH activity without major effects on proliferative rates in complete medium. PDH suppression increased reliance on extracellular lipids, and in some cell lines, reducing lipid availability uncovered a modest growth defect that could be completely reversed by providing exogenous-free fatty acids. PDH suppression also shifted the source of lipogenic acetyl-CoA from glucose to glutamine, and this compensatory pathway required a net reductive isocitrate dehydrogenase (IDH) flux to produce a source of glutamine-derived acetyl-CoA for fatty acids. By deleting the cytosolic isoform of IDH (IDH1), the enhanced contribution of glutamine to the lipogenic acetyl-CoA pool during PDHA1 suppression was eliminated, and growth was modestly suppressed.
  
  
  CONCLUSIONS
  Although PDH suppression substantially alters central carbon metabolism, the data indicate that rapid cell proliferation occurs independently of PDH activity. Our findings reveal that this central enzyme is essentially dispensable for growth and proliferation of both primary cells and established cell lines. We also identify the compensatory mechanisms that are activated under PDH deficiency, namely scavenging of extracellular lipids and lipogenic acetyl-CoA production from reductive glutamine metabolism through IDH1.
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Kartik N
authors.initials: KN
authors.lastname: Rajagopalan
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Egnatchik
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Calvaruso
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Ajla T
authors.initials: AT
authors.lastname: Wasti
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Mahesh S
authors.initials: MS
authors.lastname: Padanad
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Lindsey K
authors.initials: LK
authors.lastname: Boroughs
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Bookyung
authors.initials: B
authors.lastname: Ko
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Hensley
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Melih
authors.initials: M
authors.lastname: Acar
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Zeping
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Departments of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascual
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA ; Departments of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA ; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis