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Redox Biol. 2017 Apr;11:60-72. doi: 10.1016/j.redox.2016.11.010. Epub 2016 Nov 20.

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease.

Author information

1
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.
2
Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain.
3
Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Centre de Recherches en Cancerologie de Toulouse, Toulouse, France.
4
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.
5
Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
6
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.
7
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.
8
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.
9
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.

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.

KEYWORDS:

Ceramide; Cerebellum; Hepatosplenomegaly; Lysosomal disorders; Sphingolipids, Mitochondrial GSH

PMID:
27888692
PMCID:
PMC5123076
DOI:
10.1016/j.redox.2016.11.010
[Indexed for MEDLINE]
Free PMC Article

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