Journal Article

Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway

Gao, Xing‐Huang, Qiao, Changhong, Quinzii, Catarina M, Di Meo, Ivano, Sanchez‐Quintero, Maria J, Kleiner, Giulio, Hatzoglou, Maria, Schuelke, Markus, Ziosi, Marcello, Tadesse, Saba, Jiang, Hongfeng, Rodenburg, Richard J, Scalais, Emmanuel, Tiranti, Valeria, Willard, Belinda, Barca, Emanuele

2017

Overview

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 ADCK3 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. Synopsis Coenzyme Q (CoQ) is an electron acceptor for sulfide‐quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Lack of CoQ is here shown to cause impairment of hydrogen sulfide oxidation in vitro and in vivo . Reduced levels of CoQ in vitro cause impairment of the hydrogen sulfide oxidation pathway and increased protein persulfhydration levels. Reduced levels of CoQ in vivo impair the sulfide oxidation pathway determining accumulation of sulfides and consequent inhibition of short‐chain acyl‐CoA dehydrogenase. Graphical Abstract Coenzyme Q (CoQ) is an electron acceptor for sulfide‐quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Lack of CoQ is here shown to cause impairment of hydrogen sulfide oxidation in vitro and in vivo .

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Alkyl and Aryl Transferases - deficiency / Animals / Ataxia - physiopathology / Cells, Cultured / Coenzyme Q / CoQ10 / EMBO16 / EMBO21 / Enzymes / Fibroblasts / Fibroblasts - metabolism / Glutathione / Humans / Hydrogen sulfide / Kidney diseases / Kidneys / Kinases / Mice / Mice, Knockout / Mitochondrial Diseases - physiopathology / Muscle Weakness - physiopathology / Mutation / Oxidation / Oxidation-Reduction / Oxidation-reduction reaction / Oxidative stress / Pdss2 / Physiological aspects / Quinone Reductases - analysis / Quinones / Reductase / Renal failure / Research Article / Skin / SQR / Sulfides / Sulfides - metabolism / Supplements / Thiosulfate / Ubiquinone - deficiency / Urine