Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway

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

doi:10.15252/emmm.201606356

Cited by 66 publications

(93 citation statements)

References 63 publications

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“…In addition, and independently from Ttc19, Parl ensures CoQ biosynthesis by stabilization of Coq4, a protein required for the biosynthesis of this electron acceptor 42 . Intriguingly, the profound CoQ deficiency that we found in Parl -/brains is followed by a secondary reduction in the expression of Sqrdl, as also recently observed in models of primary CoQ defects 32,43 . This hydrophobic molecule serves essential functions in mitochondrial membranes both as an electron carrier from several metabolic pathways to Complex III and as membrane antioxidant 44,45 The Ttc19 -/mice data indicate that the CoQ deficiency is independent from the complex III defect.…”

Section: Discussionsupporting

confidence: 85%

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Parl Deficiency in Mouse Causes Coenzyme Q Depletion, Complex III Defects, and Leigh-like Syndrome

Spinazzi

Radælli

Horré

et al. 2018

Preprint

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The mitochondrial intramembrane rhomboid protease Parl has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that Parl ablation in mouse causes a striking necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional Parl deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline Parl knockouts demonstrating the vital role of Parl in neurological homeostasis. Genetic modification of two major Parl substrates, Pink1 and Pgam5, do not modify this severe neurological phenotype. Parl -/brain mitochondria are affected by defects in Complex III activity and in coenzyme Q biosynthesis. Parl is necessary for the stable expression of Ttc19, required for Complex III activity, and of Coq4, essential in coenzyme Q biosynthesis. Thus, Parl plays a previously overseen constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and Leigh-like syndrome.

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Section: Discussionsupporting

confidence: 85%

“…We also notice the significant decrease of the sulfide-CoQ oxidoreductase Sqrdl, which has been recently reported to decrease in human diseases caused by primary CoQ defects 32 .…”

Section: Mitochondrial Proteome Changes Induced By Parl Deficieny In supporting

confidence: 59%

Parl Deficiency in Mouse Causes Coenzyme Q Depletion, Complex III Defects, and Leigh-like Syndrome

Spinazzi

Radælli

Horré

et al. 2018

Preprint

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“…More recently, coenzyme Q deficiency, a classical mitochondrial disorder, has been added to the list H 2 S‐related disorders, as it was found to negatively affect the activity of the H 2 S‐metabolizing enzyme SQR (Ziosi et al, ; Luna‐Sánchez et al, ). While no direct deficiency of SQR has been described for humans, an impaired production of coenzyme Q, the cofactor of SQR, appears to correlate with low SQR protein levels (Kühl et al, ).…”

Section: Deficiencies In Cysteine Catabolismmentioning

confidence: 99%

Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism

Kohl

Mellis

Schwarz

2018

British J Pharmacology

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Cysteine is one of the two key sulfur-containing amino acids with important functions in redox homeostasis, protein functionality and metabolism. Cysteine is taken up by mammals via their diet and can also be derived from methionine via the transsulfuration pathway. The cellular concentration of cysteine is kept within a narrow range by controlling its synthesis and degradation. There are two pathways for the catabolism of cysteine leading to sulfate, taurine and thiosulfate as terminal products. The oxidative pathway produces taurine and sulfate, while the H S pathway involves different enzymatic reactions leading to the formation and clearance of H S, an important signalling molecule in mammals, resulting in thiosulfate and sulfate. Sulfite is a common intermediate in both catabolic pathways. Sulfite is considered as cytotoxic and produces neurotoxic S-sulfonates. As a result, a deficiency in the terminal steps of cysteine or H S catabolism leads to severe forms of encephalopathy with the accumulation of sulfite and H S in the body. This review links the homeostatic regulation of both cysteine catabolic pathways to sulfite and H S.

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“…Pdss2 kd / kd mice show increased blood levels of C4-C6 acylcarnitines, indicative of a defect of short-chain fatty acids oxidation caused by SCAD inhibition, however, surprisingly, we did not find CIV deficiency in the affected tissues of the Pdss2 kd / kd and Coq9 mutant mice (Luna-Sanchez et al, 2017; Ziosi et al, 2017). It is possible that in CoQ deficiency H 2 S levels are not high enough to suppress CIV activity, since patients with ethylmalonic aciduria present with a much more severe phenotype associated with CIV deficiency (Tiranti et al, 2009).…”

Section: Mammalian In Vivo Studies: the Connection Of The Disruption mentioning

confidence: 56%

“…However, the striking effects of CoQ synthesis inhibition and of CoQ supplementation on SQOR mRNA levels suggest that changes in CoQ levels modulate gene expression (Ziosi et al, 2017). There are previous evidences that CoQ affects biological processes, as lipid metabolism, inflammation, and cell signaling, through regulation of gene expression, mediated by its antioxidant function (Schmelzer et al, 2008; Fischer et al, 2016).…”

Section: Mammalian Studies In Vitro: the H2s Oxidation Pathway Is Impmentioning

confidence: 99%

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

et al. 2017

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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 Pdss2kd/kd mice, kidney, the only organ clinically affected, shows reduced SQOR levels and downstream enzymes, accumulation of H2S, and glutathione depletion. Pdss2kd/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 Coq9R239X 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. Coq9R239X 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.

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Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway

Cited by 66 publications

References 63 publications

Parl Deficiency in Mouse Causes Coenzyme Q Depletion, Complex III Defects, and Leigh-like Syndrome

Parl Deficiency in Mouse Causes Coenzyme Q Depletion, Complex III Defects, and Leigh-like Syndrome

Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism

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

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