New Insights on the Uptake and Trafficking of Coenzyme Q

Abstract

Coenzyme Q (CoQ) is an essential lipid with many cellular functions, such as electron transport for cellular respiration, antioxidant protection, redox homeostasis, and ferroptosis suppression. Deficiencies in CoQ due to aging, genetic disease, or medication can be ameliorated by high-dose supplementation. As such, an understanding of the uptake and transport of CoQ may inform methods of clinical use and identify how to better treat deficiency. Here, we review what is known about the cellular uptake and intracellular distribution of CoQ from yeast, mammalian cell culture, and rodent models, as well as its absorption at the organism level. We discuss the use of these model organisms to probe the mechanisms of uptake and distribution. The literature indicates that CoQ uptake and distribution are multifaceted processes likely to have redundancies in its transport, utilizing the endomembrane system and newly identified proteins that function as lipid transporters. Impairment of the trafficking of either endogenous or exogenous CoQ exerts profound effects on metabolism and stress response. This review also highlights significant gaps in our knowledge of how CoQ is distributed within the cell and suggests future directions of research to better understand this process.

Keywords: coenzyme Q; lipid trafficking; membrane contact sites; mitochondria transport; ubiquinone.

Figure 2

Coenzyme Q biosynthetic pathway. The dashed arrows indicate decarboxylation and hydroxylation steps that are catalyzed by unknown enzyme(s), thus resulting in an uncertainty in the order of reactions. Intermediates in the pathway include 4-HPP, 4-hydroxyphenylpyruvate; 4-HMA, 4-hydroxymandelate; 4-Hbz, 4-hydroxybenzaldehyde; 4-HB, 4-hydroxybenzoic acid; DMAPP, dimethylallyl pyrophosphate; IPP, isopentenyl pyrophosphate; HPB, 4-hydroxy-3-polyprenyl-benzoic acid; DHPB, 4,5-dihydroxy-3-polyprenylbenzoic acid; HMPB, 4-hydroxy-5-methoxy-3-polyprenylbenzoic acid; DHP, 4,5-dihydroxy-3-polyprenylphenol; DDMQH₂, 2-methoxy-6-polyprenyl-1,4-benzohydroquinone; DMQH₂, 2-methoxy-5-methyl-6-polyprenyl-1,4-benzohydroquinone; DMeQH₂, 3-methyl-6-methoxy-2-polyprenyl-1,4,5-benzenetriol; n is the number of isoprene units in the polyisoprenyl tail. Yeast can also utilize p-aminobenzoic acid as a ring precursor, and its prenylation by Coq2 produces the early intermediate 4-amino-3-polyprenyl-benzoic acid (HAB, [38]). Adapted with permission from Wang et al. [44]. Created with Biorender.com (accessed on 28 June 2023).

Figure 1

Coenzyme Q functions. (a) Mitochondrial CoQ shuttles electrons in the electron transport chain and is reduced by dehydrogenases in diverse metabolic pathways. CI, Complex I; CII, Complex II; CIII, Complex III; CIV, Complex IV; CV, Complex V; DHODH, dihydroorotate dehydrogenase; GPDH, glyceraldehyde-3-phosphate dehydrogenase; SQR, sulfide:quinone oxidoreductase; CHDH, choline dehydrogenase; PRDH, proline dehydrogenase; ETF, electron transfer flavoprotein; ETFDH, electron transfer flavoprotein dehydrogenase. (b) CoQH₂ is present in cellular membranes and lipoproteins and acts as a chain-terminating antioxidant to inhibit both the initiation and propagation steps of lipid autoxidation. CoQH₂ or ascorbate regenerate vitamin E from the tocopheroxyl radical. (c) CoQ functions in the plasma membrane redox system (PMRS) with other antioxidants, such as vitamin E and ascorbate. CoQ is reduced by NAD(P)H:quinone oxidoreductase 1 (NQO1), or NADH-cytochrome b₅ reductase (cyb5Red). (d) The CoQ reductase ferroptosis suppressor protein 1 (FSP1) regenerates CoQH₂ at the plasma membrane to terminate lipid peroxidation and suppress ferroptosis. Created with Biorender.com (accessed on 23 May 2023).

Figure 3

Yeast coq mutants are rescued with exogenous CoQ₆ but not non-isoprenoid CoQ analogues. (a) CoQ₆ was not detected in any of the coqΔ mutants. CoQ₆ (pmol/mg protein) was determined based on a CoQ₆ standard curve as described in (Tsui et al., 2019). (b) Each of the coq mutants, from coq3Δ to coq9Δ, accumulated early CoQ₆ intermediates (HHB and HAB). The amount of HHB and HAB was calculated as the area of the MS peak/mg protein. (c) Yeast mutants harboring deletions in either the COQ1 or COQ2 gene showed more robust rescue in response to exogenous CoQ₆ treatment than do the other single coq null mutants (coq3Δ–coq9Δ). (d) Additional deletions of either COQ1 or COQ2 restored the deficient CoQ₆-rescue of a coq3Δ mutant, but do not affect the phenotype observed in coq1Δ or coqΔ2 strains. Columns represent the degree of rescue (in %) ± SD of a strain compared to WT, which is defined as 100% and represented as a dashed line. Statistically significant differences between a specific coqΔ mutant and one of its counterparts (another coqΔ mutant) are denoted with numbers in parentheses on top of the columns. (1) represents differences comparing to coq1Δ, (2) represents differences comparing to coq2Δ, (3) represents differences comparing to coq3Δ, etc. Three or more independent rescue experiments were performed for every strain. Asterisks on top of the columns represent significant differences when compared to WT (* p < 0.05, ** p < 0.01, *** p < 0.001). (e) Structures of CoQ analogues. Panels (a–d) reproduced with permission from Fernandez-del-Rio et al. Free Radicals in Biology and Medicine, published by Elsevier, 2020 [18]. Created with Biorender.com (Accessed on 27 June 2023).

Figure 4

Pathways and proteins involved in trafficking of CoQ₆ to and from mitochondria. See text for the description of gene products that are involved in transport of CoQ₆ in yeast. The endoplasmic reticulum-mitochondria encounter structure (ERMES) is formed by Mdm10 and Mdm34 at the outer mitochondrial membrane, Mdm12 in the cytosol, and Mmm1 on the ER membrane. Septin filaments are hetero-oligomeric complexes composed of septin subunits, including Cdc10, Cdc3, Cdc12, Cdc11, and sometimes Shs1. PP2A, protein phosphatase 2A. Dashed lines denoted with question marks indicate postulated pathways of CoQ trafficking. Created with Biorender.com (Accessed on 25 May 2023).

Figure 5

CaCo-2 cell monolayers are used to model the uptake and transport of CoQ from the apical or lumenal side to the basolateral compartment. Created with BioRender.com (Accessed on 25 May 2023).

Figure 6

CoQ₁₀ uptake and trafficking in mammalian cells. Dashed arrows indicate CoQ movement; solid arrows indicate chemical reactions. Proteins responsible for trafficking CoQ are identified where known; proteins mediating the transport shown by dashed arrows remain to be identified. (a) Exogenous CoQ uptake and intracellular CoQ distribution are mediated by several known mechanisms in mammalian cell culture. CD36 and NPC1L1 recognize and import exogenous CoQ within brown adipose tissue and small intestine epithelial cells, respectively. The endomembrane system facilitates intracellular trafficking of CoQ between membrane-bound vesicles. Dual-localized STARD7 in the mitochondria and cytosol support endogenous CoQ biosynthesis and distribution to the plasma membrane, respectively. (b) Model of lipoprotein-associated CoQ trafficking at the blood–brain barrier. SR-B1 and RAGE regulate influx of the HDL-associated CoQ across the blood–brain barrier, while LRP-1 regulates the efflux of LDL-associated CoQ. 1, receptor-mediated endocytosis; 2, recycling to apical side via the same receptor; 3, transcytosis to basolateral side; 4, transport to lysosome; 5, recycling or efflux of CoQ to apical membrane via LDL receptor family proteins; 6, paracellular transport detected due to defects in tight junctions. HDL, high-density lipoprotein; LDL, low-density lipoprotein. Created with BioRender.com (Accessed on 28 June 2023).

Figure 7

Model for the absorption of dietary-supplemented CoQ in mice. Dashed arrows indicate CoQ distribution to tissues enriched only at high doses or IP injection. Stars in urine and feces indicate metabolites of CoQ. The ? indicates an unknown mechanism for the uptake of CoQ into the brain. VLDL—very low-density lipoprotein; IDL—intermediate-density lipoprotein; LDL—low-density lipoprotein; LPL—lipoprotein lipase. Created with BioRender.com (Accessed 31 January 2023).