Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease.
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.
['Torres|Sandra|S|', 'Matías|Nuria|N|', 'Baulies|Anna|A|', 'Nuñez|Susana|S|', 'Alarcon-Vila|Cristina|C|', 'Martinez|Laura|L|', 'Nuño|Natalia|N|', 'Fernandez|Anna|A|', 'Caballeria|Joan|J|', 'Levade|Thierry|T|', 'Gonzalez-Franquesa|Alba|A|', 'Garcia-Rovés|Pablo|P|', 'Balboa|Elisa|E|', 'Zanlungo|Silvana|S|', 'Fabrías|Gemma|G|', 'Casas|Josefina|J|', 'Enrich|Carlos|C|', 'Garcia-Ruiz|Carmen|C|', 'Fernández-Checa|José C|JC|']
D000111:Acetylcysteine D000818:Animals D002531:Cerebellum D002784:Cholesterol D005978:Glutathione D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D008247:Lysosomes D051379:Mice D018345:Mice, Knockout D008928:Mitochondria D009154:Mutation D000077296:Niemann-Pick C1 Protein D052556:Niemann-Pick Disease, Type C D010085:Oxidative Phosphorylation D011506:Proteins D011689:Purkinje Cells D033921:Vesicular Transport Proteins
Hepatosplenomegaly Cerebellum Ceramide Lysosomal disorders Sphingolipids, Mitochondrial GSH