Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.

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

doi:10.15252/emmm.201606356

Abstract

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.

Highlights

Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway
We demonstrated that CoQdeficient fibroblasts carrying mutations in different COQ genes have decreased SQR-driven respiration, which is associated with variably reduced SQR steady-state levels, depending on the severity of CoQ deficiency, and subsequent compensatory up-regulation of the levels of the downstream proteins of the pathway
The molecular abnormalities observed in COQ-mutant fibroblasts are due to reduced CoQ levels, because they can be rescued by CoQ supplementation and are partially recapitulated by pharmacological inhibition of CoQ biosynthesis via 4-NB in wild-type fibroblasts and by ADCK3 depletion in HeLa cells. 4-NB is an analogue of 4-HB and inhibitor of 4-para-hydroxybenzoate:polyprenyl transferase (COQ2; Forsman et al, 2010)

Summary

Introduction

Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Kidneys of Pdss2kd/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. 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

Methods

Results

Conclusion