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Disorders of Human Coenzyme Q10 Metabolism: an Overview

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Disorders of Human Coenzyme Q10 Metabolism: an Overview International Journal of Molecular Sciences Review Disorders of Human Coenzyme Q10 Metabolism: An Overview Iain Hargreaves 1,*, Robert A. Heaton 1 and David Mantle 2 1 School of Pharmacy, Liverpool John Moores University, L3 5UA Liverpool, UK; [email protected] 2 Pharma Nord (UK) Ltd., Telford Court, Morpeth, NE61 2DB Northumberland, UK; [email protected] * Correspondence: [email protected] Received: 19 August 2020; Accepted: 11 September 2020; Published: 13 September 2020 Abstract: Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extramitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant, plays an important role in fatty acid, pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. In view of the central role of CoQ10 in cellular metabolism, it is unsurprising that a CoQ10 deficiency is linked to the pathogenesis of a range of disorders. CoQ10 deficiency is broadly classified into primary or secondary deficiencies. Primary deficiencies result from genetic defects in the multi-step biochemical pathway of CoQ10 synthesis, whereas secondary deficiencies can occur as result of other diseases or certain pharmacotherapies. In this article we have reviewed the clinical consequences of primary and secondary CoQ10 deficiencies, as well as providing some examples of the successful use of CoQ10 supplementation in the treatment of disease. Keywords: coenzyme Q10; mitochondria; oxidative stress; antioxidant; deficiencies 1. Introduction Coenzyme Q10 (CoQ10) is a lipid-soluble molecule comprising a central benzoquinone moiety, to which is attached a 10-unit polyisoprenoid lipid tail [1] (Figure1). The benzoquinone ring contains redox active sites, whereas the polyisoprenoid chain is responsible for positioning the CoQ10 molecule within the mid-plane of the lipid bilayer of various cell membrane types. CoQ10 is usually described as a vitamin-like substance, although by definition, CoQ10 is not a vitamin, since it is produced by various tissues within the human body. The synthesis of the CoQ10 molecule comprises three major steps, namely, synthesis of the benzoquinone structure from 4-hydroxybenzoate (derived from either tyrosine or phenylalanine), synthesis of the polyisoprenoid side chain from acetyl-coenzyme A (CoA) via the mevalonate pathway, and condensation of these two structures to form coenzyme Q10; the benzoquinone ring structure is then subject to further modification via hydroxylation, methylation and decarboxylation to form CoQ10 [2]. There are several potential rate-limiting steps in the overall CoQ10 biosynthetic pathway, including synthesis of the polyisoprenoid chain (via HMG-CoA reductase) and condensation of the polyisoprenoid chain and benzoquinone ring (via prenyltransferase) [3]. CoQ10 has a number of vital cellular functions, particularly within mitochondria, but also elsewhere within the cell [1]. Within mitochondria, CoQ10 has a key role as an electron carrier (from complex I and II to complex III) in the mitochondrial electron transport chain (METC) during oxidative phosphorylation (Figure2). It is also involved (as a cofactor of the enzyme dihydroorate dehydrogenase) in the metabolism of pyrimidines, fatty acids and mitochondrial uncoupling proteins, as well as in the regulation of the mitochondrial permeability transition pore [1]. CoQ10 serves as an important lipid-soluble antioxidant protecting cellular membranes, both mitochondrial and Int. J. Mol. Sci. 2020, 21, 6695; doi:10.3390/ijms21186695 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 14 Int. J. Mol. Sci. 2020, 21, 6695 2 of 13 extra-mitochondrial (Golgi apparatus, lysosomes, endoplasmic reticulum, peroxisomes) from free radical-induced oxidative stressFigure (OS) 1. [2 The]. In chemical addition structure to acting of CoQ as an10. antioxidant directly, CoQ10 is also involved in the regeneration of the antioxidants vitamin C and vitamin E, respectively [4]. In addition,CoQ10 CoQ10 has hasa number a role as of a mediatorvital cellular of inflammation, functions, particularly a role in cholesterol within metabolismmitochondria, [5], but a role also in maintainingelsewhere within lysosomal the cell pH [1]. [6 Within], a role mitochondria, in sulphide metabolism CoQ10 has asa key a cofactor role as ofan theelectron sulphide carrier quinone (from oxidoreductasecomplex I and [II7] andto complex a role in III) amino in acidthe mitochon metabolismdrial (as electron a co-factor transport of choline chain dehydrogenase (METC) during and prolineoxidative dehydrogenase phosphorylation in the (Figure synthesis 2). It of is glycine also involved and proline (as /aarginine, cofactor respectively) of the enzyme [8,9 dihydroorate]. CoQ10 has beendehydrogenase) shown to directly in the a ffmetabolismect the expression of pyrimidi of a numbernes, fatty of genes acids [10 and]. CoQ10 mitochondrial exists in both uncoupling oxidised (ubiquinone)proteins, as well and reducedas in the (ubiquinol) regulation forms,of the andmito thechondrial normal permeability functioning of transition CoQ10 involves pore [1]. continual CoQ10 Int.inter-conversionserves J. Mol. as Sci. an 2020 important, 21 between, x FOR lipid-soluble PEER these REVIEW two forms antioxidant [1]. protecting cellular membranes, both mitochondrial2 of 14 and extra-mitochondrial (Golgi apparatus, lysosomes, endoplasmic reticulum, peroxisomes) from free radical-induced oxidative stress (OS) [2]. In addition to acting as an antioxidant directly, CoQ10 is also involved in the regeneration of the antioxidants vitamin C and vitamin E, respectively [4]. In addition, CoQ10 has a role as a mediator of inflammation, a role in cholesterol metabolism [5], a role in maintaining lysosomal pH [6], a role in sulphide metabolism as a cofactor of the sulphide quinone oxidoreductase [7] and a role in amino acid metabolism (as a co-factor of choline dehydrogenase and proline dehydrogenase in the synthesis of glycine and proline/arginine, respectively) [8,9]. CoQ10 has been shown to directly affect the expression of a number of genes [10]. CoQ10 exists in both oxidised (ubiquinone) and reduced (ubiquinol) forms, and the normal functioning of CoQ10 involves continual inter-conversion between these two forms [1]. Figure 1. The chemical structure of CoQ10.. CoQ10 has a number of vital cellular functions, particularly within mitochondria, but also elsewhere within the cell [1]. Within mitochondria, CoQ10 has a key role as an electron carrier (from complex I and II to complex III) in the mitochondrial electron transport chain (METC) during oxidative phosphorylation (Figure 2). It is also involved (as a cofactor of the enzyme dihydroorate dehydrogenase) in the metabolism of pyrimidines, fatty acids and mitochondrial uncoupling proteins, as well as in the regulation of the mitochondrial permeability transition pore [1]. CoQ10 serves as an important lipid-soluble antioxidant protecting cellular membranes, both mitochondrial and extra-mitochondrial (Golgi apparatus, lysosomes, endoplasmic reticulum, peroxisomes) from free radical-induced oxidative stress (OS) [2]. In addition to acting as an antioxidant directly, CoQ10 is also involved in the regeneration of the antioxidants vitamin C and vitamin E, respectively [4]. In addition, CoQ10 has a role as a mediator of inflammation, a role in cholesterol metabolism [5], a role in maintaining lysosomal pH [6], a role in sulphide metabolism as a cofactor of the sulphide quinone oxidoreductase [7] and a role in amino acid metabolism (as a co-factor of choline dehydrogenase and proline dehydrogenase in the synthesis of glycine and proline/arginine, respectively) [8,9]. CoQ10 has been shown to directly affect the expression of a number of genes [10]. CoQ10 exists in both oxidised (ubiquinone) and reduced (ubiquinol) forms, and the normal functioning of CoQ10 involves Figure 2. Basic schematic of the mitochondrial electron transport chain (METC), highlighting the continualFigure inter-conversion 2. Basic schematic between of the mitochondrialthese two forms electron [1]. transport chain (METC), highlighting the electron carrier function of CoQ10 in the chain. electron carrier function of CoQ10 in the chain. The daily requirement for CoQ10 is not known with certainty but has been estimated to be approximatelyThe daily 500requirement mg/day, based for CoQ10 on a total is not body known pool of wi 2000th certainty mg and averagebut has tissuebeen turnoverestimated time to be of fourapproximately days [11]. A500 small mg/day, amount based of on CoQ10 a total (approximately body pool of 2000 5 mg) mg is obtainedand average from tissue the dailyturnover diet time [11], withof four most days of [11]. the dailyA small requirement amount of beingCoQ10 synthesised (approximately within 5 mg) the body.is obtained CoQ10 from is produced the daily diet in many [11], tissues,with most being of the at particularly daily requirement high levels being in synthesi the kidney,sed heart,within skeletal the body. muscle CoQ10 and is liver produced [12]. However, in many when taking into account tissue CoQ10 levels (µg/g of tissue) together with organ weight, the liver appears to be the principal site of CoQ10 biosynthesis in the body. Optimal production occurs around 25 years of age, after which production steadily declines, with the production level at age 65 being approximately
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