Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis

Gabriel N. Valbuena, Milena Rizzardini, Sara Cimini, Alexandros P. Siskos, Caterina Bendotti, Lavinia Cantoni, Hector C. Keun

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2222-2240
JournalMolecular Neurobiology
Volume53
DOIs
Publication statusPublished - 2016

Fingerprint

Metabolomics
Amyotrophic Lateral Sclerosis
Glycolysis
Amino Acids
Energy Metabolism
Endoplasmic Reticulum Stress
Isotopes
Glutathione
Homeostasis
Phenotype
Glucose
Serum
Proteins

Keywords

  • Amino acids
  • Amyotrophic lateral sclerosis
  • Cu/Zn superoxide dismutase
  • Glutamate
  • Glutamine
  • Glycolysis
  • Motor neuron
  • NSC-34
  • Pyruvate dehydrogenase kinase 1
  • Serine

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis. / Valbuena, Gabriel N.; Rizzardini, Milena; Cimini, Sara; Siskos, Alexandros P.; Bendotti, Caterina; Cantoni, Lavinia; Keun, Hector C.

In: Molecular Neurobiology, Vol. 53, 2016, p. 2222-2240.

Research output: Contribution to journalArticle

Valbuena, Gabriel N. ; Rizzardini, Milena ; Cimini, Sara ; Siskos, Alexandros P. ; Bendotti, Caterina ; Cantoni, Lavinia ; Keun, Hector C. / Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis. In: Molecular Neurobiology. 2016 ; Vol. 53. pp. 2222-2240.
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