Open AccessCoenzyme Q deficiency causes impairment of the sulfide oxidation pathway
Author(s) -
Ziosi Marcello,
Di Meo Ivano,
Kleiner Giulio,
Gao XingHuang,
Barca Emanuele,
SanchezQuintero Maria J,
Tadesse Saba,
Jiang Hongfeng,
Qiao Changhong,
Rodenburg Richard J,
Scalais Emmanuel,
Schuelke Markus,
Willard Belinda,
Hatzoglou Maria,
Tiranti Valeria,
Quinzii Catarina M
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606356
Subject(s) - chemistry , coenzyme q – cytochrome c reductase , oxidative stress , glutathione , biochemistry , enzyme , hydrogen sulfide , antioxidant , oxidative phosphorylation , endocrinology , medicine , mitochondrion , biology , sulfur , cytochrome c , organic chemistry
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 in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK 3 depletion in HeLa cells. Kidneys of Pdss2 kd/kd mice, which only have ~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 ~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.