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

Redox Biology

dc.creatorTorres, Sandra
dc.creatorMatias, Nuria
dc.creatorBaulies, Anna
dc.creatorNuñez, Susana
dc.creatorAlarcon-Vila, Cristina
dc.creatorMartínez, Laura
dc.creatorNuno, Natalia
dc.creatorFernández, Anna
dc.creatorCaballeria, Joan
dc.creatorLevade, Thierry
dc.creatorGonzález-Franquesa, Alba
dc.creatorGarcia-Roves, Pablo
dc.creatorBalboa-Castillo, Elisa Ivana
dc.creatorZanlungo-Matsuhiro, Silvana
dc.creatorFabrias, Gemma
dc.creatorCasas, Josefina
dc.creatorEnrich, Carlos
dc.creatorGarcía-Ruíz, Carmen
dc.creatorFernández-Checa, José C
dc.date2021-08-23T22:58:34Z
dc.date2022-07-07T02:46:55Z
dc.date2021-08-23T22:58:34Z
dc.date2022-07-07T02:46:55Z
dc.date2017
dc.date.accessioned2023-08-22T03:40:35Z
dc.date.available2023-08-22T03:40:35Z
dc.identifier1150182
dc.identifier1150182
dc.identifierhttps://hdl.handle.net/10533/252343
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8316076
dc.descriptionNiemann 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. Author Keywords:Ceramide; Sphingolipids; Mitochondrial GSH; Cerebellum; Hepatosplenomegaly; Lysosomal disorders . KeyWords Plus:IMPROVES NEUROLOGICAL SYMPTOMS; CHOLESTEROL ACCUMULATION; GLUTATHIONE; DYSFUNCTION; SENSITIZES; TRANSPORT; DAMAGE; CELLS; METABOLISM; MECHANISMS
dc.descriptionRegular 2015
dc.descriptionFONDECYT
dc.descriptionFONDECYT
dc.languageeng
dc.relationhandle/10533/111557
dc.relationhandle/10533/111541
dc.relationhandle/10533/108045
dc.relationhttps://i3.investigacion.ing.uc.cl/wp-content/uploads/2017/01/JI32016n07_sci05.pdf
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile
dc.rightshttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/
dc.rightsinfo:eu-repo/semantics/article
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleMitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease
dc.titleRedox Biology
dc.typeArticulo
dc.typeinfo:eu-repo/semantics/publishedVersion


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