Cargando…

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

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 tra...

Descripción completa

Detalles Bibliográficos
Autores principales: Valbuena, Gabriel N., Rizzardini, Milena, Cimini, Sara, Siskos, Alexandros P., Bendotti, Caterina, Cantoni, Lavinia, Keun, Hector C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823370/
https://www.ncbi.nlm.nih.gov/pubmed/25963727
http://dx.doi.org/10.1007/s12035-015-9165-7
_version_ 1782425902277197824
author Valbuena, Gabriel N.
Rizzardini, Milena
Cimini, Sara
Siskos, Alexandros P.
Bendotti, Caterina
Cantoni, Lavinia
Keun, Hector C.
author_facet Valbuena, Gabriel N.
Rizzardini, Milena
Cimini, Sara
Siskos, Alexandros P.
Bendotti, Caterina
Cantoni, Lavinia
Keun, Hector C.
author_sort Valbuena, Gabriel N.
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12035-015-9165-7) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4823370
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Springer US
record_format MEDLINE/PubMed
spelling pubmed-48233702016-04-20 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. Mol Neurobiol Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12035-015-9165-7) contains supplementary material, which is available to authorized users. Springer US 2015-05-12 2016 /pmc/articles/PMC4823370/ /pubmed/25963727 http://dx.doi.org/10.1007/s12035-015-9165-7 Text en © The Author(s) 2015 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Article
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
title Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis
title_full Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis
title_fullStr Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis
title_full_unstemmed Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis
title_short Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis
title_sort metabolomic analysis reveals increased aerobic glycolysis and amino acid deficit in a cellular model of amyotrophic lateral sclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823370/
https://www.ncbi.nlm.nih.gov/pubmed/25963727
http://dx.doi.org/10.1007/s12035-015-9165-7
work_keys_str_mv AT valbuenagabrieln metabolomicanalysisrevealsincreasedaerobicglycolysisandaminoaciddeficitinacellularmodelofamyotrophiclateralsclerosis
AT rizzardinimilena metabolomicanalysisrevealsincreasedaerobicglycolysisandaminoaciddeficitinacellularmodelofamyotrophiclateralsclerosis
AT ciminisara metabolomicanalysisrevealsincreasedaerobicglycolysisandaminoaciddeficitinacellularmodelofamyotrophiclateralsclerosis
AT siskosalexandrosp metabolomicanalysisrevealsincreasedaerobicglycolysisandaminoaciddeficitinacellularmodelofamyotrophiclateralsclerosis
AT bendotticaterina metabolomicanalysisrevealsincreasedaerobicglycolysisandaminoaciddeficitinacellularmodelofamyotrophiclateralsclerosis
AT cantonilavinia metabolomicanalysisrevealsincreasedaerobicglycolysisandaminoaciddeficitinacellularmodelofamyotrophiclateralsclerosis
AT keunhectorc metabolomicanalysisrevealsincreasedaerobicglycolysisandaminoaciddeficitinacellularmodelofamyotrophiclateralsclerosis