期刊
EMBO MOLECULAR MEDICINE
卷 9, 期 1, 页码 96-111出版社
WILEY-BLACKWELL
DOI: 10.15252/emmm.201606356
关键词
coenzyme Q; CoQ10; Pdss2; SQR; sulfides
资金
- Cell Lines and DNA Bank of Pediatric Movement Disorders and Neurodegenerative Diseases of the Telethon Network of Genetic Biobanks [GTB12001J]
- Eurobiobank Network
- NIH [P01 HD080642-01]
- NIH Clinical Translational Science Award (CTSA) [UL1TR000040, NIH R37-DK060596, R01-DK053307, 1S10RR031537-01]
- Pierfranco e Luisa Mariani Foundation, Milan (Italy)
- Muscle Dystrophy Association (MDA)
- Department of Defense (DOD)
- Italian Ministry of Health [79/GR-2010-2306756]
Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation invitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2(kd/kd) mice, which only have similar to 15% residual CoQ concentrations and are clinically affected, showed (i) reduced protein levels of SQR and downstream enzymes, (ii) accumulation of hydrogen sulfides, and (iii) glutathione depletion. These abnormalities were not present in brain, which maintains similar to 30% residual CoQ and is clinically unaffected. In Pdss2(kd/kd) mice, we also observed low levels of plasma and urine thiosulfate and increased blood C4-C6 acylcarnitines. We propose that impairment of the sulfide oxidation pathway induced by decreased levels of CoQ causes accumulation of sulfides and consequent inhibition of short-chain acyl-CoA dehydrogenase and glutathione depletion, which contributes to increased oxidative stress and kidney failure.
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