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CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway.
Biochim Biophys Acta Mol Basis Dis. 2018 11; 1864(11):3708-3722.BB

Abstract

Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ10 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 CoQ10 supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 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.

Authors+Show Affiliations

Department of Neurology, Columbia University Medical Center, New York, NY, United States.Department of Neurology, Columbia University Medical Center, New York, NY, United States.Department of Neurology, Columbia University Medical Center, New York, NY, United States.Department of Neurology, Columbia University Medical Center, New York, NY, United States.Department of Pathology, Columbia University Medical Center, New York, NY, United States.Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain.Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY, United States.Department of Neurology, Columbia University Medical Center, New York, NY, United States.Department of Neurology, Columbia University Medical Center, New York, NY, United States.Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain.Department of Neurology, Columbia University Medical Center, New York, NY, United States. Electronic address: cmq2101@cumc.columbia.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30251690

Citation

Kleiner, Giulio, et al. "CoQ10 Supplementation Rescues Nephrotic Syndrome Through Normalization of H2S Oxidation Pathway." Biochimica Et Biophysica Acta. Molecular Basis of Disease, vol. 1864, no. 11, 2018, pp. 3708-3722.
Kleiner G, Barca E, Ziosi M, et al. CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway. Biochim Biophys Acta Mol Basis Dis. 2018;1864(11):3708-3722.
Kleiner, G., Barca, E., Ziosi, M., Emmanuele, V., Xu, Y., Hidalgo-Gutierrez, A., Qiao, C., Tadesse, S., Area-Gomez, E., Lopez, L. C., & Quinzii, C. M. (2018). CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway. Biochimica Et Biophysica Acta. Molecular Basis of Disease, 1864(11), 3708-3722. https://doi.org/10.1016/j.bbadis.2018.09.002
Kleiner G, et al. CoQ10 Supplementation Rescues Nephrotic Syndrome Through Normalization of H2S Oxidation Pathway. Biochim Biophys Acta Mol Basis Dis. 2018;1864(11):3708-3722. PubMed PMID: 30251690.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway. AU - Kleiner,Giulio, AU - Barca,Emanuele, AU - Ziosi,Marcello, AU - Emmanuele,Valentina, AU - Xu,Yimeng, AU - Hidalgo-Gutierrez,Agustin, AU - Qiao,Changhong, AU - Tadesse,Saba, AU - Area-Gomez,Estela, AU - Lopez,Luis C, AU - Quinzii,Catarina M, Y1 - 2018/09/06/ PY - 2018/05/18/received PY - 2018/08/03/revised PY - 2018/09/05/accepted PY - 2018/9/27/pubmed PY - 2018/12/12/medline PY - 2018/9/26/entrez KW - CoQ deficiency KW - Coenzyme Q(10) KW - Mitochondria KW - Oxidative stress KW - Sulfides SP - 3708 EP - 3722 JF - Biochimica et biophysica acta. Molecular basis of disease JO - Biochim Biophys Acta Mol Basis Dis VL - 1864 IS - 11 N2 - Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ10 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 CoQ10 supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 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. SN - 1879-260X UR - https://www.unboundmedicine.com/medline/citation/30251690/CoQ10_supplementation_rescues_nephrotic_syndrome_through_normalization_of_H2S_oxidation_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(18)30337-5 DB - PRIME DP - Unbound Medicine ER -