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.

Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration

“…Buildup of cholesterol seems to directly impair also mitochondrial GSH import, leading to mitochondrial GSH depletion (Torres et al . ). In addition, the authors show that GSH ethyl ester (GSH‐EE), but not N‐acetylcysteine, rescues the mitochondrial GSH pool in both liver and brain of Npc1 −/− mice and in fibroblasts from NPC patients.…”

Fundamentals of CNS energy metabolism and alterations in lysosomal storage diseases

“…A recent study showed that increasing mitochondrial GSH levels by intraperitoneal administration of GSH ethyl ester protected brain cells of NPC1‐deficient mice from oxidative stress, mitochondrial impairment and cell death, and increased maximal life span and survival of these animals (Torres et al . ). These findings underscore the potential of mitochondrially targeted therapies for the treatment of NPCD patients.…”

Adenosine and Adenosine A2AReceptors as Targets for the Treatment of Niemann Pick Type C Disease

“…19 In addition to this, NPC1 mutation induced an increased cholesterol level in mitochondria, leading to alterations in the function of this organelle and in energy metabolism. [20][21][22] Abnormal mitochondrial morphology, depolarization of mitochondrial membrane potential (mMP), respiratory chain deficit, and impaired adenosine triphosphate (ATP) production have been shown in NPC1-depleted Chinese hamster ovary cells as well as in the brain of a mouse model of NPC1 13,21,23 (Balb/c NPC1 À/À model, hereafter indicated as NPC1 mice). Moreover, in an NPC1 cell model, it was demonstrated that an excessive activation and impaired progression of the autophagy could be responsible for the abnormal mitochondrial clearance and of the (most probably subsequent) accumulation of depolarized and fragmented mitochondria.…”