title: Metabolic reprogramming during neuronal differentiation.
abstract: Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1α. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate-glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K-Akt-mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation.
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.|Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Agostini
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.|Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta Campus, Catanzaro 88100, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Romeo
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.
authors.forename: M V
authors.initials: MV
authors.lastname: Niklison-Chirou
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Elia
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.
authors.forename: D
authors.initials: D
authors.lastname: Dinsdale
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.
authors.forename: N
authors.initials: N
authors.lastname: Morone
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Knight
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.|Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.|Biochemistry Laboratory IDI-IRCC, c/o Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy.
authors.forename: G
authors.identifier: 0000-0001-9428-5972
authors.initials: G
authors.lastname: Melino
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D004272:DNA, Mitochondrial / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D060847:Metabolic Engineering; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D005947:Glucose; D051274:Glucose Transporter Type 3; D005721:Glutamate-Cysteine Ligase; D018698:Glutamic Acid; D005973:Glutamine; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C485290:Ppargc1a protein, mouse; C560749:GCLM protein, mouse