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Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation
- Source :
- Redox Biology, Vol 45, Iss, Pp 102052-(2021), Dipòsit Digital de la UB, Universidad de Barcelona, Redox Biology, Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
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 Stard1f/f mice but not Stard1ΔHep 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.<br />Graphical abstract Image 1<br />Highlights • Cholesterol accumulates in mitochondria in liver and brain from Npc1−/− mice and fibroblasts from NPC patients. • Affected organs of Npc1−/− mice and fibroblasts from NPC patients exhibit increased STARD1 expression. • Decreased expression of ACDase is found in affected organs of Npc1−/− mice and fibroblasts from NPC patients. • ACDase overexpression represses STARD1 expression and improves mitochondrial function and oxidative stress in fibroblasts from NPC patients.
- Subjects :
- 0301 basic medicine
Programmed cell death
Medicine (General)
Acid Ceramidase
QH301-705.5
Clinical Biochemistry
Oxidative phosphorylation
Mitochondrion
medicine.disease_cause
Biochemistry
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
R5-920
Downregulation and upregulation
ddc:570
Acid ceramiase
medicine
Animals
Humans
Niemann-Pick diseases
ddc:610
Biology (General)
Mice, Knockout
Chemistry
Cholesterol
Organic Chemistry
Niemann-Pick Disease, Type C
Malalties de Niemann-Pick
Phosphoproteins
Mitochondria
Cell biology
030104 developmental biology
NPC disease
Oxidative stress
lipids (amino acids, peptides, and proteins)
NPC1
Mitochondrial function
Lysosomes
Colesterol
030217 neurology & neurosurgery
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 45
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....6e50c700036096ca9a8578df1bcd8277