title: Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease.
abstract: Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/-mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/-mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/-mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/-mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/-mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Torres
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Matías
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Baulies
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Nuñez
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alarcon-Vila
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martinez
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Nuño
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Fernandez
authors.affiliation: Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Caballeria
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Centre de Recherches en Cancerologie de Toulouse, Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Gonzalez-Franquesa
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garcia-Rovés
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Elisa
authors.initials: E
authors.lastname: Balboa
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
authors.affiliation: 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.
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabrías
authors.affiliation: 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.
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.affiliation: Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Enrich
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain; Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States. Electronic address: cgrbam@iibb.csic.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garcia-Ruiz
authors.affiliation: Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain; Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States. Electronic address: checa229@yahoo.com.
authors.forename: José C
authors.initials: JC
authors.lastname: Fernández-Checa
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C497045:Npc2 protein, mouse; D011506:Proteins; D033921:Vesicular Transport Proteins; D002784:Cholesterol; D005978:Glutathione; D000111:Acetylcysteine
keywords: Ceramide; Cerebellum; Hepatosplenomegaly; Lysosomal disorders; Sphingolipids, Mitochondrial GSH