TY - JOUR
T1 - Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease
AU - Torres, Sandra
AU - Matías, Nuria
AU - Baulies, Anna
AU - Nuñez, Susana
AU - Alarcon-Vila, Cristina
AU - Martinez, Laura
AU - Nuño, Natalia
AU - Fernandez, Anna
AU - Caballeria, Joan
AU - Levade, Thierry
AU - Gonzalez-Franquesa, Alba
AU - Garcia-Rovés, Pablo
AU - Balboa, Elisa
AU - Zanlungo, Silvana
AU - Fabrías, Gemma
AU - Casas, Josefina
AU - Enrich, Carlos
AU - Garcia-Ruiz, Carmen
AU - Fernández-Checa, José C.
N1 - Publisher Copyright:
© 2016 The Authors
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - Ceramide
KW - Cerebellum
KW - Hepatosplenomegaly
KW - Lysosomal disorders
KW - Sphingolipids, Mitochondrial GSH
UR - http://www.scopus.com/inward/record.url?scp=84996844004&partnerID=8YFLogxK
U2 - 10.1016/j.redox.2016.11.010
DO - 10.1016/j.redox.2016.11.010
M3 - Artículo
C2 - 27888692
AN - SCOPUS:84996844004
SN - 2213-2317
VL - 11
SP - 60
EP - 72
JO - Redox Biology
JF - Redox Biology
ER -