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S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.
Goicoechea, Leire; Torres, Sandra; Fàbrega, Laura; Barrios, Mónica; Núñez, Susana; Casas, Josefina; Fabrias, Gemma; García-Ruiz, Carmen; Fernández-Checa, José C.
Afiliación
  • Goicoechea L; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en
  • Torres S; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en
  • Fàbrega L; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en
  • Barrios M; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en
  • Núñez S; Centro de Investigación Biomédica en Red (CIBEREHD), Barcelona, Spain.
  • Casas J; Research Unit on BioActive Molecules (RUBAM), Departament de Química Orgànica Biològica, Institut D'Investigacions Químiques I Ambientals de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
  • Fabrias G; Research Unit on BioActive Molecules (RUBAM), Departament de Química Orgànica Biològica, Institut D'Investigacions Químiques I Ambientals de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
  • García-Ruiz C; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en
  • Fernández-Checa JC; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en
Redox Biol ; 72: 103150, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38599016
ABSTRACT
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by impaired motor coordination due to neurological defects and cerebellar dysfunction caused by the accumulation of cholesterol in endolysosomes. Besides the increase in lysosomal cholesterol, mitochondria are also enriched in cholesterol, which leads to decreased membrane fluidity, impaired mitochondrial function and loss of GSH, and has been shown to contribute to the progression of NPC disease. S-Adenosyl-l-methionine (SAM) regulates membrane physical properties through the generation of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) methylation and functions as a GSH precursor by providing cysteine in the transsulfuration pathway. However, the role of SAM in NPC disease has not been investigated. Here we report that Npc1-/- mice exhibit decreased brain SAM levels but unchanged S-adenosyl-l-homocysteine content and lower expression of Mat2a. Brain mitochondria from Npc1-/- mice display decreased mitochondrial GSH levels and liquid chromatography-high resolution mass spectrometry analysis reveal a lower PC/PE ratio in mitochondria, contributing to increased mitochondrial membrane order. In vivo treatment of Npc1-/- mice with SAM restores SAM levels in mitochondria, resulting in increased PC/PE ratio, mitochondrial membrane fluidity and subsequent replenishment of mitochondrial GSH levels. In vivo SAM treatment improves the decline of locomotor activity, increases Purkinje cell survival in the cerebellum and extends the average and maximal life spam of Npc1-/- mice. These findings identify SAM as a potential therapeutic approach for the treatment of NPC disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: S-Adenosilmetionina / Encéfalo / Membranas Mitocondriales / Enfermedad de Niemann-Pick Tipo C / Glutatión / Fluidez de la Membrana Límite: Animals Idioma: En Revista: Redox Biol Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: S-Adenosilmetionina / Encéfalo / Membranas Mitocondriales / Enfermedad de Niemann-Pick Tipo C / Glutatión / Fluidez de la Membrana Límite: Animals Idioma: En Revista: Redox Biol Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos