The Role of Sulfide Oxidation Impairment in the Pathogenesis of Primary CoQ Deficiency

Abstract

Coenzyme Q (CoQ) is a lipid present in all cell membranes. One of the multiple metabolic functions of CoQ is to transport electrons in the reaction catalyzed by sulfide:quinone oxidoreductase (SQOR), the first enzyme of the oxidation pathway of sulfides (hydrogen sulfide, H₂S). Early evidence of a defect in the metabolism of H₂S in primary CoQ deficiency came from yeast studies in Schizosaccharomyces pombe strains defective for dps1 and ppt1 (homologs of PDSS1 and COQ2, respectively), which have H₂S accumulation. Our recent studies in human skin fibroblasts and in murine models of primary CoQ deficiency show that, also in mammals, decreased CoQ levels cause impairment of H₂S oxidation. Patient fibroblasts carrying different mutations in genes encoding proteins involved in CoQ biosynthesis show reduced SQOR activity and protein levels proportional to the levels of CoQ. In Pdss2^kd/kd mice, kidney, the only organ clinically affected, shows reduced SQOR levels and downstream enzymes, accumulation of H₂S, and glutathione depletion. Pdss2^kd/kd mice have also low levels of thiosulfate in plasma and urine, and increased C4-C6 acylcarnitines in blood, due to inhibition of short-chain acyl-CoA dehydrogenase. Also in Coq9^R239X mice, the symptomatic organ, cerebrum, shows accumulation of H₂S, reduced SQOR, increase in thiosulfate sulfurtransferase and sulfite oxidase, and reduction in the levels of glutathione and glutathione enzymes, leading to alteration of the biosynthetic pathways of glutamate, serotonin, and catecholamines. Coq9^R239X mice have also reduced blood pressure, possible consequence of H₂S-induced vasorelaxation. Since liver is not clinically affected in Pdss2 and Coq9 mutant mice, the effects of the impairment of H₂S oxidation in this organ were not investigated, despite its critical role in metabolism. In conclusion, in vitro and in vivo studies of CoQ deficient models provide evidence of tissue-specific H₂S oxidation impairment, an additional pathomechanism that should be considered in the understanding and treatment of primary CoQ deficiency.

Keywords: CoQ; H2S; SQOR; coenzyme Q; sulfide:quinone oxidoreductase; sulfides.

Figure 1

Schematic representation of sulfides (H₂S) synthesis and oxidation pathways. The enzymes involve in the trans-sulfuration pathway are cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and PLP-independent 3-mercaptopyruvate sulfurtransferase (3MST). The enzymes involved in the mitochondrial H₂S oxidation pathway are sulfide:quinone oxidoreductase (SQOR), sulfur dioxygenase (SDO; also known as ETHE1 or persulfide dioxygenase), sulfite oxidase (SO), thiosulfate sulfurtransferase or rhodanese (TST), and thiosulfate reductase (TR) (Tables A1, A2).

Figure 2

Schematic representation of CoQ biosynthesis. Coenzyme Q₁₀ (CoQ₁₀) is the predominant form of CoQ in humans and is synthesized in the mitochondrial inner membrane. CoQ₁₀ is composed of a benzoquinone ring, derived from tyrosine or phenylalanine, and an isoprenoid side chain, synthetized in multiple steps by the enzyme decaprenyl diphosphate synthase. PHB-polyprenyl transferase (COQ2) is responsible for the condensation of decaprenyl diphosphate and para-hydroxybenzoate (PHB). The benzoate ring is then modified by at least six enzymes, which catalyze methylation, decarboxylation, and hydroxylation reactions to synthesize CoQ₁₀ (Tables A1, A2).