A novel inborn error of the coenzyme Q10 biosynthesis pathway: cerebellar ataxia and static encephalomyopathy due to COQ5 C‐methyltransferase deficiency

Malicdan, May Christine V.; Vilboux, Thierry; Ben‐Zeev, Bruria; Guo, Jennifer; Eliyahu, Aviva; Pode‐Shakked, Ben; Dori, Amir; Kakani, Sravan; Chandrasekharappa, Settara C.; Ferreira, Carlos R.; Shelestovich, Natalia; Marek‐Yagel, Dina; Pri‐Chen, Hadass; Blatt, Ilan; Niederhuber, John E.; He, Langping; Toro, Camilo; Taylor, Robert W.; Deeken, John F.; Yardeni, Tal; Wallace, Douglas C.; Gahl, William A.; Anikster, Yair

doi:10.1002/humu.23345

Cited by 47 publications

(32 citation statements)

References 61 publications

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“…Thus, human COQ5 is an ortholog of yeast Coq5, but can rescue yeast only when the other yeast Coq partner proteins are present and the CoQ synthome is assembled. Primary CoQ 10 deficiency has been recently diagnosed due to a partial loss of function of COQ5 [ 69 ]. The deficiency is shown to be due to a duplication of the COQ5 gene, and that due to alternative splicing appears to generate an unstable COQ5 mRNA with a long 3′-UTR.…”

Section: Yeast and Human Genes Essential For Coq Biosynthesismentioning

confidence: 99%

“…Steady state levels of the COQ5 polypeptide were dramatically decreased in fibroblasts from the affected homozygous patients as compared with controls. The affected patients had variable degrees of cerebellar ataxia, and showed a modest decrease in the levels of CoQ 10 in peripheral blood leukocytes, and a more dramatic decrease in CoQ 10 levels in a skeletal muscle biopsy [ 69 ]. The reduction in CoQ 10 levels is consistent with the observation that decreases in COQ5-containing mitochondrial protein complex impairs the production of CoQ 10 [ 70 ].…”

Section: Yeast and Human Genes Essential For Coq Biosynthesismentioning

confidence: 99%

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Coenzyme Q10 deficiencies: pathways in yeast and humans

Awad¹,

Bradley²,

Fernández-del-Rio³

et al. 2018

Essays in Biochemistry

115

141

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Coenzyme Q (ubiquinone or CoQ) is an essential lipid that plays a role in mitochondrial respiratory electron transport and serves as an important antioxidant. In human and yeast cells, CoQ synthesis derives from aromatic ring precursors and the isoprene biosynthetic pathway. Saccharomyces cerevisiae coq mutants provide a powerful model for our understanding of CoQ biosynthesis. This review focusses on the biosynthesis of CoQ in yeast and the relevance of this model to CoQ biosynthesis in human cells. The COQ1–COQ11 yeast genes are required for efficient biosynthesis of yeast CoQ. Expression of human homologs of yeast COQ1–COQ10 genes restore CoQ biosynthesis in the corresponding yeast coq mutants, indicating profound functional conservation. Thus, yeast provides a simple yet effective model to investigate and define the function and possible pathology of human COQ (yeast or human gene involved in CoQ biosynthesis) gene polymorphisms and mutations. Biosynthesis of CoQ in yeast and human cells depends on high molecular mass multisubunit complexes consisting of several of the COQ gene products, as well as CoQ itself and CoQ intermediates. The CoQ synthome in yeast or Complex Q in human cells, is essential for de novo biosynthesis of CoQ. Although some human CoQ deficiencies respond to dietary supplementation with CoQ, in general the uptake and assimilation of this very hydrophobic lipid is inefficient. Simple natural products may serve as alternate ring precursors in CoQ biosynthesis in both yeast and human cells, and these compounds may act to enhance biosynthesis of CoQ or may bypass certain deficient steps in the CoQ biosynthetic pathway.

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Section: Yeast and Human Genes Essential For Coq Biosynthesismentioning

confidence: 99%

Section: Yeast and Human Genes Essential For Coq Biosynthesismentioning

confidence: 99%

Coenzyme Q10 deficiencies: pathways in yeast and humans

Awad¹,

Bradley²,

Fernández-del-Rio³

et al. 2018

Essays in Biochemistry

115

141

View full text Add to dashboard Cite

show abstract

“…So far, pathogenic mutations for 9 of the 11 genes currently known to participate in human CoQ biosynthesis have been identified, with an estimated 125,000 individuals affected worldwide [ 7 , [19] , [20] , [21] ]. CoQ deficiency is associated with numerous symptoms, including nephrotic syndrome, infantile encephalomyopathy, ataxia and cerebellar atrophy [ 7 , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] ]. Like mitochondrial disease syndrome (MDS), primary CoQ deficiency is often a multi-systems disorder with heterogeneous clinical manifestations.…”

Section: Introductionmentioning

confidence: 99%

Micellization of coenzyme Q by the fungicide caspofungin allows for safe intravenous administration to reach extreme supraphysiological concentrations

Wang¹,

Hekimi²

2020

Redox Biology

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Coenzyme Q 10 (CoQ 10 ; also known as ubiquinone) is a vital, redox-active membrane component that functions as obligate electron transporter in the mitochondrial respiratory chain, as cofactor in other enzymatic processes and as antioxidant. CoQ 10 supplementation has been widely investigated for treating a variety of acute and chronic conditions in which mitochondrial function or oxidative stress play a role. In addition, it is used as replacement therapy in patients with CoQ deficiency including inborn primary CoQ 10 deficiency due to mutations in CoQ 10 -biosynthetic genes as well as secondary CoQ 10 deficiency, which is frequently observed in patients with mitochondrial disease syndrome and in other conditions. However, despite many tests and some promising results, whether CoQ 10 treatment is beneficial in any indication has remained inconclusive. Because CoQ 10 is highly insoluble, it is only available in oral formulations, despite its very poor oral bioavailability. Using a novel model of CoQ-deficient cells, we screened a library of FDA-approved drugs for an activity that could increase the uptake of exogenous CoQ 10 by the cell. We identified the fungicide caspofungin as capable of increasing the aqueous solubility of CoQ 10 by several orders of magnitude. Caspofungin is a mild surfactant that solubilizes CoQ 10 by forming nano-micelles with unique properties favoring stability and cellular uptake. Intravenous administration of the formulation in mice achieves unprecedented increases in CoQ 10 plasma levels and in tissue uptake, with no observable toxicity. As it contains only two safe components (caspofungin and CoQ 10 ), this injectable formulation presents a high potential for clinical safety and efficacy.

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“…With the exception of Coq3, patients have been reported with mutations in all other components of the CoQ multi-subunit complex [ 249 , 250 ]. These patients can be treated with CoQ 10 supplementation with partial success.…”

Section: Pathological Mutations In Respiratory Chain and Atp Synthmentioning

confidence: 99%

Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces cerevisiae

Franco

Bremner

Barros

2020

Life

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The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in elucidating the functions of numerous yeast nuclear gene products with human homologs that affect a large number of metabolic and biological processes, including those housed in mitochondria. These include structural and catalytic subunits of enzymes and protein factors that impinge on the biogenesis of the respiratory chain. This article will review what is currently known about the genetics and clinical phenotypes of mitochondrial diseases of the respiratory chain and ATP synthase, with special emphasis on the contribution of information gained from pet mutants with mutations in nuclear genes that impair mitochondrial respiration. Our intent is to provide the yeast mitochondrial specialist with basic knowledge of human mitochondrial pathologies and the human specialist with information on how genes that directly and indirectly affect respiration were identified and characterized in yeast.

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A novel inborn error of the coenzyme Q10 biosynthesis pathway: cerebellar ataxia and static encephalomyopathy due to COQ5 C‐methyltransferase deficiency

Abstract: Primary coenzyme Q10 (CoQ 10

Cited by 47 publications

References 61 publications

Coenzyme Q10 deficiencies: pathways in yeast and humans

Coenzyme Q10 deficiencies: pathways in yeast and humans

Micellization of coenzyme Q by the fungicide caspofungin allows for safe intravenous administration to reach extreme supraphysiological concentrations

Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces cerevisiae

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