Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation

Abstract

Niemann-Pick type C (NPC) disease, a lysosomal storage disorder caused by defective NPC1/NPC2 function, results in the accumulation of cholesterol and glycosphingolipids in lysosomes of affected organs, such as liver and brain. Moreover, increase of mitochondrial cholesterol (mchol) content and impaired mitochondrial function and GSH depletion contribute to NPC disease. However, the underlying mechanism of mchol accumulation in NPC disease remains unknown. As STARD1 is crucial in intramitochondrial cholesterol trafficking and acid ceramidase (ACDase) has been shown to regulate STARD1, we explored the functional relationship between ACDase and STARD1 in NPC disease. Liver and brain of Npc1 −/− mice presented a significant increase in mchol levels and STARD1 expression. U18666A, an amphiphilic sterol that inhibits lysosomal cholesterol efflux, increased mchol levels in hepatocytes from Stard1 f/f mice but not Stard1 ΔHep mice. We dissociate the induction of STARD1 expression from endoplasmic reticulum stress, and establish an inverse relationship between ACDase and STARD1 expression and LRH-1 levels. Hepatocytes from Npc1 +/+ mice treated with U18666A exhibited increased mchol accumulation, STARD1 upregulation and decreased ACDase expression, effects that were reversed by cholesterol extraction with 2-hydroxypropyl-β-cyclodextrin. Moreover, transfection of fibroblasts from NPC patients with ACDase, decreased STARD1 expression and mchol accumulation, resulting in increased mitochondrial GSH levels, improved mitochondrial functional performance, decreased oxidative stress and protected NPC fibroblasts against oxidative stress-mediated cell death. Our results demonstrate a cholesterol-dependent inverse relationship between ACDase and STARD1 and provide a novel approach to target the accumulation of cholesterol in mitochondria in NPC disease.

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

“…Meanwhile, mutations in NPC Intracellular Cholesterol Transporter 1 or 2 (NPC1 or NPC2) alter cellular cholesterol trafficking and lipid metabolism disruption, leading to Niemann-Pick's disease type C1 and C2 [91]. Recently, Torres et al have shown that ASAH1 is downregulated in patients with Niemann-Pick's disease type C1 [92]. They have also observed that the overexpression of ASAH1 improves mitochondrial function and reduces oxidative stress by decreasing STARD1.…”

“…Studies in hepatocytes demonstrated that the decrease in GSH activity was correlated with increases in the activity of nSMase2, and this was related to an IL-1β hyperresponsiveness, increasing the pro-inflammatory response [195]. Interestingly, recent study has demonstrated that ASAH1 overexpression increase GSH levels and reduce oxidative stress in fibroblasts derived from Niemann-Pick's disease type C1 [92].…”

Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling

“… 14 Oxidative stress, mitophagy and mitochondrial dynamics including fusion and fission were found to play crucial roles in COPD and serve as therapeutic targets. 15 , 16 Of various metabolic pathways, mitochondria play a key role in lipid metabolism, cholesterol homeostasis and interactions among intracellular organelles, 17 , 18 , 19 although the exact mechanism in COPD remains unclear. The aim of the present study was to investigate alterations of cholesterol metabolism in COPD and potential mechanisms by which cholesterol regulated mitochondrial function in lung epithelial cells.…”

“…11 STARD3 was reported to be localized on the membrane of late endosomes, regulate cholesterol transport from endosomes to mitochondria and increase secondary accumulation of cholesterol in the outer mitochondrial membrane. 17,18 STARD3 overexpression increased cholesterol redistribution to the mitochondria, causing over-production of reactive oxygen species and enhancement of steroidogenesis. 12,13 Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis and development of lung diseases.…”

Polyploid giant cancer cells are dependent on cholesterol for progeny formation through amitotic division

“…The LDL-cholesterol is then transported to the late endosomes where hydrolysis by acid lipases releases free cholesterol, mediated by Niemann-Pick proteins. Defects in this process result in a lysosomal storage disorder that was recently shown to involve a cholesterol-dependent inverse relationship with ASAH1 16 . We therefore investigated how ASAH1 inhibition affects the intracellular distribution of cholesterol upon LCL521 treatment by staining cultures with filipin for visual evaluation 17 .…”