Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation
Sandra Torres,
Estel Solsona-Vilarrasa,
Susana Nuñez,
Nuria Matías,
Naroa Insausti-Urkia,
Fernanda Castro,
Mireia Casasempere,
Gemma Fabriás,
Josefina Casas,
Carlos Enrich,
José C. Fernández-Checa,
Carmen Garcia-Ruiz
Affiliations
Sandra Torres
Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain
Estel Solsona-Vilarrasa
Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain
Susana Nuñez
Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain
Nuria Matías
Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain
Naroa Insausti-Urkia
Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain
Fernanda Castro
Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
Mireia Casasempere
Research Unit on BioActive Molecules (RUBAM), Departament de Química Orgànica Biològica, Institut d'Investigacions Químiques i Ambientals de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
Gemma Fabriás
Research Unit on BioActive Molecules (RUBAM), Departament de Química Orgànica Biològica, Institut d'Investigacions Químiques i Ambientals de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
Josefina Casas
Research Unit on BioActive Molecules (RUBAM), Departament de Química Orgànica Biològica, Institut d'Investigacions Químiques i Ambientals de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
Carlos Enrich
Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036, Barcelona, Spain; Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain
José C. Fernández-Checa
Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain; Research Center for ALPD, Keck School of Medicine, Univerisity of Southern California, Los Angeles, CA, USA; Corresponding author. Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain.
Carmen Garcia-Ruiz
Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain; Research Center for ALPD, Keck School of Medicine, Univerisity of Southern California, Los Angeles, CA, USA; Corresponding author. Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain.
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.
