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Oxidative Damage Compromises Energy Metabolism in the Axonal Degeneration Mouse Model of X-Adrenoleukodystrophy

Aims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhib... Full description

Journal Title: Antioxidants & Redox Signaling 2011-10-15, Vol.15 (8), p.295-2107
Main Author: Galino, Jorge
Other Authors: Ruiz, Montserrat , Fourcade, Stéphane , Schlüter, Agatha , López-Erauskin, Jone , Guilera, Cristina , Jove, Mariona , Naudi, Alba , García-Arumí, Elena , Andreu, Antoni L. , Starkov, Anatoly A. , Pamplona, Reinald , Ferrer, Isidre , Portero-Otin, Manuel , Pujol, Aurora
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Mary Ann Liebert, Inc
ID: ISSN: 1523-0864
Link: https://www.ncbi.nlm.nih.gov/pubmed/21453200
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title: Oxidative Damage Compromises Energy Metabolism in the Axonal Degeneration Mouse Model of X-Adrenoleukodystrophy
format: Article
creator:
  • Galino, Jorge
  • Ruiz, Montserrat
  • Fourcade, Stéphane
  • Schlüter, Agatha
  • López-Erauskin, Jone
  • Guilera, Cristina
  • Jove, Mariona
  • Naudi, Alba
  • García-Arumí, Elena
  • Andreu, Antoni L.
  • Starkov, Anatoly A.
  • Pamplona, Reinald
  • Ferrer, Isidre
  • Portero-Otin, Manuel
  • Pujol, Aurora
subjects:
  • Adenosine Triphosphate - metabolism
  • Adrenoleukodystrophy - genetics
  • Adrenoleukodystrophy - metabolism
  • Animals
  • Antioxidants
  • ATP Binding Cassette Transporter, Sub-Family D, Member 1
  • ATP-Binding Cassette Transporters - genetics
  • ATP-Binding Cassette Transporters - metabolism
  • Blotting, Western
  • Cells, Cultured
  • Disease Models, Animal
  • Electrophoresis, Gel, Two-Dimensional
  • Energy Metabolism - genetics
  • Energy Metabolism - physiology
  • Estrès oxidatiu
  • Glutathione - metabolism
  • Humans
  • Malalties neurodegeneratives
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NAD - metabolism
  • Neurodegenerative diseases
  • Original Research Communications
  • Oxidative stress
  • Oxidative Stress - genetics
  • Oxidative Stress - physiology
  • Proteomics
  • Pyruvate Kinase - genetics
  • Pyruvate Kinase - metabolism
ispartof: Antioxidants & Redox Signaling, 2011-10-15, Vol.15 (8), p.295-2107
description: Aims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade. Results: In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1 − mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH. Innovation: Treating Abcd1 − mice with the antioxidants N-acetylcysteine and α-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage. Conclusion: Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy. Antioxid. Redox Signal. 15, 2095–2107.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 1523-0864
fulltext: fulltext
issn:
  • 1523-0864
  • 1557-7716
url: Link


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titleOxidative Damage Compromises Energy Metabolism in the Axonal Degeneration Mouse Model of X-Adrenoleukodystrophy
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creatorGalino, Jorge ; Ruiz, Montserrat ; Fourcade, Stéphane ; Schlüter, Agatha ; López-Erauskin, Jone ; Guilera, Cristina ; Jove, Mariona ; Naudi, Alba ; García-Arumí, Elena ; Andreu, Antoni L. ; Starkov, Anatoly A. ; Pamplona, Reinald ; Ferrer, Isidre ; Portero-Otin, Manuel ; Pujol, Aurora
creatorcontribGalino, Jorge ; Ruiz, Montserrat ; Fourcade, Stéphane ; Schlüter, Agatha ; López-Erauskin, Jone ; Guilera, Cristina ; Jove, Mariona ; Naudi, Alba ; García-Arumí, Elena ; Andreu, Antoni L. ; Starkov, Anatoly A. ; Pamplona, Reinald ; Ferrer, Isidre ; Portero-Otin, Manuel ; Pujol, Aurora
descriptionAims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade. Results: In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1 − mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH. Innovation: Treating Abcd1 − mice with the antioxidants N-acetylcysteine and α-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage. Conclusion: Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy. Antioxid. Redox Signal. 15, 2095–2107.
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subjectAdenosine Triphosphate - metabolism ; Adrenoleukodystrophy - genetics ; Adrenoleukodystrophy - metabolism ; Animals ; Antioxidants ; ATP Binding Cassette Transporter, Sub-Family D, Member 1 ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette Transporters - metabolism ; Blotting, Western ; Cells, Cultured ; Disease Models, Animal ; Electrophoresis, Gel, Two-Dimensional ; Energy Metabolism - genetics ; Energy Metabolism - physiology ; Estrès oxidatiu ; Glutathione - metabolism ; Humans ; Malalties neurodegeneratives ; Male ; Mice ; Mice, Inbred C57BL ; NAD - metabolism ; Neurodegenerative diseases ; Original Research Communications ; Oxidative stress ; Oxidative Stress - genetics ; Oxidative Stress - physiology ; Proteomics ; Pyruvate Kinase - genetics ; Pyruvate Kinase - metabolism
ispartofAntioxidants & Redox Signaling, 2011-10-15, Vol.15 (8), p.295-2107
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1Ruiz, Montserrat
2Fourcade, Stéphane
3Schlüter, Agatha
4López-Erauskin, Jone
5Guilera, Cristina
6Jove, Mariona
7Naudi, Alba
8García-Arumí, Elena
9Andreu, Antoni L.
10Starkov, Anatoly A.
11Pamplona, Reinald
12Ferrer, Isidre
13Portero-Otin, Manuel
14Pujol, Aurora
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0Oxidative Damage Compromises Energy Metabolism in the Axonal Degeneration Mouse Model of X-Adrenoleukodystrophy
1Antioxidants & Redox Signaling
addtitleAntioxid Redox Signal
descriptionAims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade. Results: In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1 − mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH. Innovation: Treating Abcd1 − mice with the antioxidants N-acetylcysteine and α-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage. Conclusion: Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy. Antioxid. Redox Signal. 15, 2095–2107.
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0Adenosine Triphosphate - metabolism
1Adrenoleukodystrophy - genetics
2Adrenoleukodystrophy - metabolism
3Animals
4Antioxidants
5ATP Binding Cassette Transporter, Sub-Family D, Member 1
6ATP-Binding Cassette Transporters - genetics
7ATP-Binding Cassette Transporters - metabolism
8Blotting, Western
9Cells, Cultured
10Disease Models, Animal
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12Energy Metabolism - genetics
13Energy Metabolism - physiology
14Estrès oxidatiu
15Glutathione - metabolism
16Humans
17Malalties neurodegeneratives
18Male
19Mice
20Mice, Inbred C57BL
21NAD - metabolism
22Neurodegenerative diseases
23Original Research Communications
24Oxidative stress
25Oxidative Stress - genetics
26Oxidative Stress - physiology
27Proteomics
28Pyruvate Kinase - genetics
29Pyruvate Kinase - metabolism
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titleOxidative Damage Compromises Energy Metabolism in the Axonal Degeneration Mouse Model of X-Adrenoleukodystrophy
authorGalino, Jorge ; Ruiz, Montserrat ; Fourcade, Stéphane ; Schlüter, Agatha ; López-Erauskin, Jone ; Guilera, Cristina ; Jove, Mariona ; Naudi, Alba ; García-Arumí, Elena ; Andreu, Antoni L. ; Starkov, Anatoly A. ; Pamplona, Reinald ; Ferrer, Isidre ; Portero-Otin, Manuel ; Pujol, Aurora
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1Adrenoleukodystrophy - genetics
2Adrenoleukodystrophy - metabolism
3Animals
4Antioxidants
5ATP Binding Cassette Transporter, Sub-Family D, Member 1
6ATP-Binding Cassette Transporters - genetics
7ATP-Binding Cassette Transporters - metabolism
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9Cells, Cultured
10Disease Models, Animal
11Electrophoresis, Gel, Two-Dimensional
12Energy Metabolism - genetics
13Energy Metabolism - physiology
14Estrès oxidatiu
15Glutathione - metabolism
16Humans
17Malalties neurodegeneratives
18Male
19Mice
20Mice, Inbred C57BL
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22Neurodegenerative diseases
23Original Research Communications
24Oxidative stress
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26Oxidative Stress - physiology
27Proteomics
28Pyruvate Kinase - genetics
29Pyruvate Kinase - metabolism
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7Naudi, Alba
8García-Arumí, Elena
9Andreu, Antoni L.
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1Ruiz, Montserrat
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6Jove, Mariona
7Naudi, Alba
8García-Arumí, Elena
9Andreu, Antoni L.
10Starkov, Anatoly A.
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issue8
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issn1523-0864
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notesThese authors contributed equally to this work.
abstractAims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade. Results: In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1 − mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH. Innovation: Treating Abcd1 − mice with the antioxidants N-acetylcysteine and α-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage. Conclusion: Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy. Antioxid. Redox Signal. 15, 2095–2107.
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