title: Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis.
abstract: Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The mechanisms through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics and stable isotope tracers to examine metabolic changes in a well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our findings indicate that wt and G93ASOD1 expression both enhanced glucose metabolism under serum deprivation. However, in wtSOD1 cells, this phenotype increased supply of amino acids for protein and glutathione synthesis, while in G93ASOD1 cells it was associated with death, aerobic glycolysis, and a broad dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to induction of pyruvate dehydrogenase kinase 1. Our study thus provides novel insight into the role of deranged energy metabolism as a cause of poor adaptation to stress and a promoter of neural cell damage in the presence of mutant SOD1. Furthermore, the metabolic alterations we report may help explain why mitochondrial dysfunction and impairment of the endoplasmic reticulum stress response are frequently seen in ALS.
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, South Kensington, London, SW7 2AZ, UK.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Valbuena
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156, Milan, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Rizzardini
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cimini
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, South Kensington, London, SW7 2AZ, UK.
authors.forename: Alexandros P
authors.initials: AP
authors.lastname: Siskos
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156, Milan, Italy. lavinia.cantoni@marionegri.it.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Cantoni
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, South Kensington, London, SW7 2AZ, UK. h.keun@imperial.ac.uk.
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
mesh_terms: D000332:Aerobiosis; D000409:Alanine / Q000378:metabolism; D000596:Amino Acids / Q000172:deficiency*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D016895:Culture Media, Serum-Free; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019289:Pyruvic Acid / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D000596:Amino Acids; D016895:Culture Media, Serum-Free; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; D050505:Mutant Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D005973:Glutamine; D019289:Pyruvic Acid; D013482:Superoxide Dismutase; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3; D053179:Caspase 7; D005947:Glucose; D000409:Alanine
keywords: Amino acids; Amyotrophic lateral sclerosis; Cu/Zn superoxide dismutase; Glutamate; Glutamine; Glycolysis; Motor neuron; NSC-34; Pyruvate dehydrogenase kinase 1; Serine