CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome.

Ramy Ka Sayed,Holger Prokisch,Tatjana M Hildebrandt,Germaine Escames,Ángela Santos‐Fandila,Agustín Hidalgo‐Gutiérrez,Darío Acuña‐Castroviejo,Miguel Romero,Felix Distelmaier,Marta Luna‐Sánchez,Luis C López,Markus Schuelke,Julio Chaves‐Serrano,Juan Duarte,Eliana Barriocanal‐Casado

doi:10.15252/emmm.201606345

Abstract

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9 R239X mice, the deficit in SQR induces an increase in thiosulfate sulfurtransferase and sulfite oxidase, as well as modifications in the levels of thiols. As a result, biosynthetic pathways of glutamate, serotonin, and catecholamines were altered in the cerebrum, and the blood pressure was reduced. Therefore, this study reveals the reduction in SQR activity as one of the pathomechanisms associated with CoQ deficiency syndrome.

Highlights

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it has several other functions in the cellular metabolism
Because CoQ acts as an electron acceptor in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR) in the mitochondrial sulfide oxidation pathway, we first evaluated whether the deficit in CoQ could affect mitochondrial H2S metabolism in these mouse models
Our study demonstrates that primary CoQ deficiency is associated with a disruption of the mitochondrial hydrogen sulfide oxidation pathway, which may be a new pathomechanism associated with this syndrome and may contribute to explain its clinical heterogeneity

Summary

Introduction

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9R239X mice, the deficit in SQR induces an increase in thiosulfate sulfurtransferase and sulfite oxidase, as well as modifications in the levels of thiols. This study reveals the reduction in SQR activity as one of the pathomechanisms associated with CoQ deficiency syndrome

Methods

Results

Discussion

Conclusion