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CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway
- Source :
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1864:3708-3722
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q(10) (CoQ(10)) deficiency and is very responsive to CoQ(10) supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ(10) supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ biosynthesis regulatory protein COQ8A. While CoQ(10) supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ(10) antioxidant effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress.
- Subjects :
- 0301 basic medicine
Mitochondrial Diseases
Nephrotic Syndrome
Antioxidant
Ubiquinone
medicine.medical_treatment
Mitochondrion
Kidney
medicine.disease_cause
Antioxidants
Mice
chemistry.chemical_compound
Oxidoreductases Acting on Sulfur Group Donors
Hydrogen Sulfide
chemistry.chemical_classification
Muscle Weakness
Chemistry
food and beverages
Mitochondria
Coenzyme Q(10)
medicine.anatomical_structure
Molecular Medicine
Oxidation-Reduction
Metabolic Networks and Pathways
medicine.medical_specialty
Mice, Transgenic
Sulfides
Article
03 medical and health sciences
Internal medicine
medicine
Animals
Humans
Molecular Biology
Coenzyme Q10
Reactive oxygen species
Alkyl and Aryl Transferases
Metabolism
medicine.disease
Disease Models, Animal
Oxidative Stress
030104 developmental biology
Endocrinology
Ataxia
CoQ deficiency
Reactive Oxygen Species
Oxidative stress
HeLa Cells
Kidney disease
Subjects
Details
- ISSN :
- 09254439
- Volume :
- 1864
- Database :
- OpenAIRE
- Journal :
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Accession number :
- edsair.doi.dedup.....54170f2eef01f0d5309ca509f61cfd3d