CoQ(10) supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway 机翻标题: 暂无翻译,请尝试点击翻译按钮。

来源
Biochimica et biophysica acta. Molecular basis of disease: BBA
年/卷/期
2018 / 1864 / 11
页码
3708-3722
ISSN号
0925-4439
作者单位
Univ Granada, Dept Physiol, Fac Med, Granada, Spain;Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, New York, NY USA;Columbia Univ, Dept Neurol, Med Ctr, 630 W 168th St,P&S 4-424A, New York, NY 10032 USA;Columbia Univ, Dept Neurol, Med Ctr, 630 W 168th St,P&S 4-424A, New York, NY 10032 USA;Univ Granada, Dept Physiol, Fac Med, Granada, Spain;Columbia Univ, Dept Neurol, Med Ctr, 630 W 168th St,P&S 4-424A, New York, NY 10032 USA;Columbia Univ, Dept Neurol, Med Ctr, 630 W 168th St,P&S 4-424A, New York, NY 10032 USA;Columbia Univ, Dept Neurol, Med Ctr, 630 W 168th St,P&S 4-424A, New York, NY 10032 USA;Columbia Univ, Dept Neurol, Med Ctr, 630 W 168th St,P&S 4-424A, New York, NY 10032 USA;Columbia Univ, Dept Neurol, Med Ctr, 630 W 168th St,P&S 4-424A, New York, NY 10032 USA;Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA;
作者
Hidalgo-Gutierrez, Agustin;Qiao, Changhong;Tadesse, Saba;Area-Gomez, Estela;Lopez, Luis C.;Quinzii, Catarina M.;Kleiner, Giulio;Barca, Emanuele;Ziosi, Marcello;Emmanuele, Valentina;Xu, Yimeng;
摘要
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.
机翻摘要
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关键词/主题词
Coenzyme Q(10);CoQ deficiency;Mitochondria;Oxidative stress;Sulfides;
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