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Co-enzyme Q10, also known as ubiquinone, is prevalent in the mitochondria of cells, where it plays important roles in metabolic processes. Coenzyme Q10 is involved in the production of energy ATP in the mitochondria of all cells. It is both synthesised in the body and consumed in the diet where it is absorbed in the small intestine and passes to the lymphatics and then to the blood and tissues.

It is a powerful antioxidant in cell membranes and lipoproteins and helps convert carbohydrates and fats into energy. Within the cell CoQ10 works with an enzyme within the mitochondria to reattach the phosphate group again making ATP. It is a continuous recycling system. As it performs its work CoQ10 becomes a powerful antioxidant in the process.

CoQ10 declines with age so it is particularly important as a supplement. It is particularly important in cells that have high-energy requirements such as those of the heart that are particularly sensitive to CoQ10 deficiency.

Statins are well known to lower CoQ10 levels to the heart, suggesting any person on statins may benefit from CoQ10 supplementation.

As CoQ10 is lipid or fat soluble, it is advisable to take this product with a meal containing fat. Coenzyme Q10 has also been utilized as an active ingredient in cosmeceuticals and as an inactive ingredient in sunscreen formulations.

When applied topically in skincare products it demonstrates some ability to reduce oxidative stress in the skin, [29] delay signs of intrinsic skin aging, reverse signs of extrinsic skin aging, [30] [31] assist in fading dyspigmentation , [32] [33] increase stability of certain sunscreen actives, [34] increase the SPF of sunscreens, [35] and afford some infrared protection to sunscreens.

CoQ 10 has also been used in in vitro fertilization and oocyte cryopreservation as a pretreatment to improve ovarian response and embryo quality in women with decreased ovarian reserve. Coenzyme Q 10 has potential to inhibit the effects of theophylline as well as the anticoagulant warfarin ; coenzyme Q 10 may interfere with warfarin's actions by interacting with cytochrome p enzymes thereby reducing the INR , a measure of blood clotting.

Coenzyme Q 10 should be avoided in patients currently taking warfarin due to the increased risk of clotting. The oxidized structure of CoQ 10 is shown below.

The various kinds of Coenzyme Q may be distinguished by the number of isoprenoid subunits in their side-chains. The most common coenzyme Q in human mitochondria is CoQ Q refers to the quinone head and 10 refers to the number of isoprene repeats in the tail.

The molecule below has three isoprenoid units and would be called Q 3. In its pure state, it is an orange-coloured lipophile powder, and has no taste nor odour. The initial two reactions occur in mitochondria , the endoplasmic reticulum , and peroxisomes , indicating multiple sites of synthesis in animal cells.

An important enzyme in this pathway is HMG-CoA reductase , usually a target for intervention in cardiovascular complications. The "statin" family of cholesterol-reducing medications inhibits HMG-CoA reductase. One possible side effect of statins is decreased production of CoQ 10 , which may be connected to the development of myopathy and rhabdomyolysis.

However, the role statins play in CoQ deficiency is controversial. Although statins reduce blood levels of CoQ, studies on the effects of muscle levels of CoQ are yet to come. CoQ supplementation also does not reduce side effects of statin medications.

Genes involved include PDSS1 , PDSS2 , COQ2 , and ADCK3 COQ8 , CABC1. Organisms other than human use somewhat different source chemicals to produce the benzoquinone structure and the isoprene structure. For example, the bacteria E. coli produces the former from chorismate and the latter from a non- mevalonate source.

The common yeast S. cerevisiae , however, derives the former from either chorismate or tyrosine and the latter from mevalonate. Most organisms share the common 4-hydroxybenzoate intermediate, yet again uses different steps to arrive at the "Q" structure.

CoQ 10 is a crystalline powder insoluble in water. Absorption follows the same process as that of lipids; the uptake mechanism appears to be similar to that of vitamin E , another lipid-soluble nutrient. This process in the human body involves secretion into the small intestine of pancreatic enzymes and bile , which facilitates emulsification and micelle formation required for absorption of lipophilic substances.

Exogenous CoQ 10 is absorbed from the small intestine and is best absorbed if taken with a meal. Serum concentration of CoQ 10 in fed condition is higher than in fasting conditions. Data on the metabolism of CoQ 10 in animals and humans are limited.

After the withdrawal of CoQ 10 supplementation, the levels return to normal within a few days, irrespective of the type of formulation used. Some reports have been published on the pharmacokinetics of CoQ The plasma peak can be observed 2—6 hours after oral administration, depending mainly on the design of the study.

In some studies, a second plasma peak also was observed at approximately 24 hours after administration, probably due to both enterohepatic recycling and redistribution from the liver to circulation. used deuterium-labeled crystalline CoQ10 to investigate pharmacokinetics in humans and determined an elimination half-time of 33 hours.

The importance of how drugs are formulated for bioavailability is well known. In order to find a principle to boost the bioavailability of CoQ 10 after oral administration, several new approaches have been taken; different formulations and forms have been developed and tested on animals and humans.

Nanoparticles have been explored as a delivery system for various drugs, such as improving the oral bioavailability of drugs with poor absorption characteristics.

A successful approach is to use the emulsion system to facilitate absorption from the gastrointestinal tract and to improve bioavailability. Emulsions of soybean oil lipid microspheres could be stabilised very effectively by lecithin and were used in the preparation of softgel capsules.

In one of the first such attempts, Ozawa et al. performed a pharmacokinetic study on beagles in which the emulsion of CoQ 10 in soybean oil was investigated; about twice the plasma CoQ 10 level than that of the control tablet preparation was determined during administration of a lipid microsphere.

with oil-based softgel capsules in a later study on dogs, [54] the significantly increased bioavailability of CoQ 10 was confirmed for several oil-based formulations in most other studies. Facilitating drug absorption by increasing its solubility in water is a common pharmaceutical strategy and also has been shown to be successful for CoQ Various approaches have been developed to achieve this goal, with many of them producing significantly better results over oil-based softgel capsules in spite of the many attempts to optimize their composition.

In , G. Festenstein was the first to isolate a small amount of CoQ 10 from the lining of a horse's gut at Liverpool , England. In subsequent studies the compound was briefly called substance SA , it was deemed to be quinone , and it was noted that it could be found from many tissues of a number of animals.

In , Frederick L. Crane and colleagues at the University of Wisconsin—Madison Enzyme Institute isolated the same compound from mitochondrial membranes of beef heart and noted that it transported electrons within mitochondria.

They called it Q for short as it was a quinone. In , its full chemical structure was reported by D. Wolf and colleagues working under Karl Folkers at Merck in Rahway.

Green and colleagues belonging to the Wisconsin research group suggested that ubiquinone should be called either mitoquinone or coenzyme Q due to its participation to the mitochondrial electron transport chain. In , A. Mellors and A. Tappel at the University of California were the first to show that reduced CoQ 6 was an effective antioxidant in cells.

In s Peter D. Mitchell enlarged upon the understanding of mitochondrial function via his theory of electrochemical gradient , which involves CoQ 10 , and in late s studies of Lars Ernster enlargened upon the importance of CoQ 10 as an antioxidant.

The s witnessed a steep rise in the number of clinical trials involving CoQ Detailed reviews on occurrence of CoQ 10 and dietary intake were published in Despite the scientific community's great interest in this compound, however, a very limited number of studies have been performed to determine the contents of CoQ 10 in dietary components.

The first reports on this aspect were published in , but the sensitivity and selectivity of the analytical methods at that time did not allow reliable analyses, especially for products with low concentrations.

Dairy products are much poorer sources of CoQ 10 than animal tissues. Among vegetables, parsley and perilla are the richest CoQ 10 sources, but significant differences in their CoQ 10 levels may be found in the literature.

Broccoli , grapes , and cauliflower are modest sources of CoQ Most fruit and berries represent a poor to very poor source of CoQ 10 , with the exception of avocados , which have a relatively high CoQ 10 content.

In the developed world, the estimated daily intake of CoQ 10 has been determined at 3—6 mg per day, derived primarily from meat. Contents move to sidebar hide. Article Talk. Read Edit View history.

Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item. Download as PDF Printable version. Random mutagenesis and selection with menadione and sodium azide as inhibitors of the respiratory system generated mutants that overcame the growth inhibition with increased CoQ 10 production.

tumefaciens was used for two up-scaling steps L and L and produced CoQ 10 to a cellular content of 8. CoQ 10 content and titer were elevated upon controlling the concentration of the carbon substrate sucrose and optimizing pH and dissolved oxygen levels Ha et al.

sphaeroides has been employed for L fermentation in which under phosphate limitation a titer of 1. sphaeroides fermentation has been realized commercially as it also benefits from the fact that CoQ production can operate with non-toxic wastewater He et al.

Metabolic engineering allows for improving production rationally in native CoQ 10 producers and for enabling CoQ 10 production in microorganism that do not possess a native CoQ biosynthesis pathway Lee et al.

CoQ 10 has been produced in metabolically engineered eukaryotes and prokaryotes, but as there are less studies about eukaryotic producers and their CoQ 10 content is not competitive with most bacterial production hosts, the following sections will only focus on the latter.

coli is a natural CoQ 8 producer and merely the expression of a heterologous decaprenyl diphosphate synthase is required for CoQ 10 production since the polyprenyl transferase UbiA promiscuously accepts polyprenyl diphosphates of different lengths Cheng and Li , as was shown before Martínez et al.

coli synthesizes both, menaquinone and ubiquinone, with menaquinone biosynthesis being nonessential under aerobic conditions.

Blocking the menaquinone pathway in addition to expression of dxs and ubiA and supplementation of pyruvate and 4-HBA boosted CoQ 8 content 4-fold. Growth was not affected under aerobic conditions by the disruption of menaquinone biosynthesis Xu et al. CoQ 10 production by this industrially important organism has received attention some years ago Table 1 Zahiri et al.

sphaeroides proved to be superior hosts for CoQ 10 production. coli should not be underestimated. This was achieved by optimized heterologous expression of MVA pathway genes and screening several heterologous Idi enzymes to improve IPP supply, overexpression of endogenous and exogenous MK pathway genes and enhancing the flux from chorismate to 1,4-dihydroxynaphthoate, the direct precursor for demethylmenaquinone Gao et al.

Studies on native CoQ 10 producers that have been genetically engineered for its overproduction are quite rare with exception of R. This purple photosynthetic bacterium emerged as the most promising organism for CoQ 10 production in recent years and will therefore be the focus here Table 1.

In one approach, genes that code for enzymes of the aerobic respiration chain were deleted due to relationship between CoQ 10 synthesis and respiration chain activity. In another study, deletion of the gene for the only known phosphotransferase system PTS in R.

Metabolic bottlenecks in the ubiquinone pathway of R. sphaeroides were identified to be UbiE, UbiH, and UbiG. UbiA was not rate-limiting contrary to observations for E.

coli and A. tumefaciens Zhang et al. Although not fully understood, heterologous expression of Vitreoscilla hemoglobin vgb slightly improved the titer in this R. sphaeroides strain Lu et al. A bacterium natively lacking CoQ biosynthesis has recently been engineered for CoQ 10 production Table 1 Burgardt et al.

Previously, C. glutamicum was engineered for high-level production of the aromatic CoQ 10 precursor 4-HBA Kitade et al. Two steps were required to enable CoQ 10 production by the 4-HBA producing C.

glutamicum strain. First, overproduction of the prenyl precursor of CoQ 10 , decaprenyl diphosphate DPP , was achieved by heterologous expression of DPP synthase gene ddsA from Paracoccus denitrificans Burgardt et al.

Second, genes for the whole ubiquinone pathway from E. coli were expressed and the resulting strain produced 0. Although the titer was low, this is the first proof-of-concept of producing CoQ 10 by a microorganism lacking native CoQ biosynthesis.

The fact that C. glutamicum has been used safely for more than 50 years in fermentative amino acid production, which is operated at a scale of 6 million tons per year Wendisch , forecasts that optimization of CoQ 10 production by this bacterium holds large potential.

Previous engineering of C. glutamicum for high-level production of aromatic compounds including the CoQ 10 precursor 4-HBA Lee and Wendisch as well as for products derived from the MEP pathway Heider et al. glutamicum and to gain an in-depth understanding of CoQ 10 biosynthesis in the respective donor microbes.

CoQ is a key component in eukaryotic and bacterial cells as it is required for energy generation while also fulfilling numerous other functions.

Future research has to fully elucidate CoQ biosynthesis since some parts of CoQ biosynthesis remain uncharacterized, e.

Recent advances, however, have been made in the understanding of the UbiD-UbiX system in bacteria, the diversity of CoQ hydroxylases, and especially, the supramolecular organization of enzymes that finalize the aromatic ring modification towards CoQ. Regarding the latter, the structural characterization and stoichiometry of the involved Ubi or Coq proteins are still missing, but hydroxylases and methyltransferases as well as associated lipid-binding proteins have been identified.

In terms of microbial production of CoQ 10 , further research on the rational improvement of CoQ 10 production is required. Although employment of mutagenized natural CoQ 10 producers and process optimization led to impressive CoQ 10 titers, the underlying mechanisms have not been understood.

Metabolic engineering will not only enable the use of renewable resources for CoQ 10 production and improve CoQ 10 titers and productivities, but rational pathway reconstruction will help to expand the knowledge about the CoQ biosynthesis.

Abby SS, Kazemzadeh K, Vragniau C et al Advances in bacterial pathways for the biosynthesis of ubiquinone. Biochim Biophys Acta Bioenerg Article CAS PubMed Google Scholar.

Alcázar-Fabra M, Navas P, Brea-Calvo G Coenzyme Q biosynthesis and its role in the respiratory chain structure. Biochim Biophys Acta BBA Bioenerg — Article CAS Google Scholar. Allan CM, Awad AM, Johnson JS et al Identification of Coq11, a new coenzyme Q biosynthetic protein in the CoQ-synthome in Saccharomyces cerevisiae.

J Biol Chem — Article CAS PubMed PubMed Central Google Scholar. Arenas-Jal M, Suñé-Negre JM, García-Montoya E Coenzyme Q10 supplementation: efficacy, safety, and formulation challenges. Compr Rev Food Sci Food Saf — Aussel L, Pierrel F, Loiseau L et al Biosynthesis and physiology of coenzyme Q in bacteria.

Biochim Biophys Acta — Averesch NJH, Rothschild LJ Metabolic engineering of Bacillus subtilis for production of para -aminobenzoic acid—unexpected importance of carbon source is an advantage for space application.

Microb Biotechnol — Ayer A, Fazakerley DJ, Suarna C et al Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q. Redox Biol Barker JL, Frost JW Microbial synthesis of p -hydroxybenzoic acid from glucose. Biotechnol Bioeng — Baschiera E, Sorrentino U, Calderan C et al The multiple roles of coenzyme Q in cellular homeostasis and their relevance for the pathogenesis of coenzyme Q deficiency.

Free Radic Biol Med — Bekker M, Kramer G, Hartog AF et al Changes in the redox state and composition of the quinone pool of Escherichia coli during aerobic batch-culture growth.

Microbiology — Burgardt A, Moustafa A, Persicke M et al Coenzyme Q 10 biosynthesis established in the non-ubiquinone containing Corynebacterium glutamicum by metabolic engineering.

Front Bioeng Biotechnol. Article PubMed PubMed Central Google Scholar. Cheng W, Li W Structural insights into ubiquinone biosynthesis in membranes.

Science — Cirilli I, Damiani E, Dludla PV et al Role of coenzyme Q 10 in health and disease: an update on the last 10 years — Antioxidants Clomburg JM, Qian S, Tan Z et al The isoprenoid alcohol pathway, a synthetic route for isoprenoid biosynthesis.

Proc Natl Acad Sci — Cluis CP, Ekins A, Narcross L et al Identification of bottlenecks in Escherichia coli engineered for the production of CoQ Metab Eng — Farmer WR, Liao JC Precursor balancing for metabolic engineering of lycopene production in Escherichia coli.

Biotechnol Prog — Fernández-Del-Río L, Clarke CF Coenzyme Q biosynthesis: an update on the origins of the benzenoid ring and discovery of new ring precursors. Metabolites Gao Q, Chen H, Wang G et al Highly efficient production of menaquinone-7 from glucose by metabolically engineered Escherichia coli.

ACS Synth Biol — George KW, Thompson MG, Kim J et al Integrated analysis of isopentenyl pyrophosphate IPP toxicity in isoprenoid-producing Escherichia coli.

Göttl VL, Schmitt I, Braun K et al CRISPRi-library-guided target identification for engineering carotenoid production by Corynebacterium glutamicum.

Microorganisms Gutierrez-Mariscal FM, Perez-Martinez P, Delgado-Lista J et al Mediterranean diet supplemented with coenzyme Q10 induces postprandial changes in p53 in response to oxidative DNA damage in elderly subjects.

Age — Ha S, Kim S, Seo J et al a Controlling the sucrose concentration increases coenzyme Q10 production in fed-batch culture of Agrobacterium tumefaciens. Appl Microbiol Biotechnol — Ha S-J, Kim S-Y, Seo J-H et al b Optimization of culture conditions and scale-up to pilot and plant scales for coenzyme Q 10 production by Agrobacterium tumefaciens.

Hajj Chehade M, Pelosi L, Fyfe CD et al A soluble metabolon synthesizes the isoprenoid lipid ubiquinone. Cell Chem Biol — He CH, Xie LX, Allan CM et al Coenzyme Q supplementation or over-expression of the yeast Coq8 putative kinase stabilizes multi-subunit Coq polypeptide complexes in yeast coq null mutants.

Biochim Biophys Acta BBA Mol Cell Biol Lipids — He S, Lu H, Zhang G, Ren Z Production of coenzyme Q 10 by purple non-sulfur bacteria: current development and future prospect. J Clean Prod Heider SAE, Peters-Wendisch P, Wendisch VF et al Metabolic engineering for the microbial production of carotenoids and related products with a focus on the rare C50 carotenoids.

Henke NA, Wendisch VF Improved astaxanthin production with Corynebacterium glutamicum by application of a membrane fusion protein.

Mar Drugs Article CAS PubMed Central Google Scholar. Henke NA, Wichmann J, Baier T et al Patchoulol production with metabolically engineered Corynebacterium glutamicum.

Genes — Huang M, Gibson F Biosynthesis of 4-aminobenzoate in Escherichia coli. J Bacteriol — Huang H, Levin EJ, Liu S et al Structure of a membrane-embedded prenyltransferase homologous to UBIAD1. PLoS Biol e Kalén A, Appelkvist E-L, Dallner G Age-related changes in the lipid compositions of rat and human tissues.

Lipids — Article PubMed Google Scholar. Kallscheuer N, Marienhagen J Corynebacterium glutamicum as platform for the production of hydroxybenzoic acids. Microb Cell Factories Kawamukai M Biosynthesis of coenzyme Q in eukaryotes.

Biosci Biotechnol Biochem — Kawamukai M Biosynthesis and applications of prenylquinones. Kazemzadeh K, Hajj Chehade M, Hourdoir G et al The biosynthetic pathway of ubiquinone contributes to pathogenicity of Francisella novicida. J Bacteriol ee Kien NB, Kong I-S, Lee M-G, Kim JK Coenzyme Q 10 production in a l reactor by a mutant strain of Rhodobacter sphaeroides.

J Ind Microbiol Biotechnol — Kim T-S, Yoo J-H, Kim S-Y et al Screening and characterization of an Agrobacterium tumefaciens mutant strain producing high level of coenzyme Q Process Biochem — Kitade Y, Hashimoto R, Suda M et al Production of 4-hydroxybenzoic acid by an aerobic growth-arrested bioprocess using metabolically engineered Corynebacterium glutamicum.

Appl Environ Microbiol. Koma D, Yamanaka H, Moriyoshi K et al Production of p -Aminobenzoic acid by metabolically engineered Escherichia coli. Krömer JO, Nunez-Bernal D, Averesch NJH et al Production of aromatics in Saccharomyces cerevisiae —a feasibility study.

J Biotechnol — Kubota T, Watanabe A, Suda M et al Production of para -aminobenzoate by genetically engineered Corynebacterium glutamicum and non-biological formation of an N -glucosyl byproduct. Lapointe CP, Stefely JA, Jochem A et al Multi-omics reveal specific targets of the RNA-binding protein Puf3p and its orchestration of mitochondrial biogenesis.

Cell Syst Latimer S, Keene SA, Stutts LR et al A dedicated flavin-dependent monooxygenase catalyzes the hydroxylation of demethoxyubiquinone into ubiquinone coenzyme Q in Arabidopsis. J Biol Chem. Lee J, Wendisch VF Biotechnological production of aromatic compounds of the extended shikimate pathway from renewable biomass.

Lee PT, Hsu AY, Ha HT, Clarke CF A C -methyltransferase involved in both ubiquinone and menaquinone biosynthesis: isolation and identification of the Escherichia coli ubiE gene.

Lee B-J, Lin Y-C, Huang Y-C et al The relationship between coenzyme Q10, oxidative stress, and antioxidant enzymes activities and coronary artery disease.

Sci World J —8. Lee SQE, Tan TS, Kawamukai M, Chen ES Cellular factories for coenzyme Q 10 production. Microb Cell Factories — Lenzen C, Wynands B, Otto M et al High-yield production of 4-hydroxybenzoate from glucose or glycerol by an engineered Pseudomonas taiwanensis VLB Front Bioeng Biotechnol Li W Bringing bioactive compounds into membranes: the UbiA superfamily of intramembrane aromatic prenyltransferases.

Trends Biochem Sci — Li C, Swofford CA, Rückert C et al Heterologous production of α-Carotene in Corynebacterium glutamicum using a multi-copy chromosomal integration method. Bioresour Technol Liao C, Ayansola H, Ma Y et al Advances in enhanced menaquinone-7 production from Bacillus subtilis. Article Google Scholar.

Liu H, Sun Y, Ramos KRM et al Combination of Entner-Doudoroff pathway with MEP increases isoprene production in engineered Escherichia coli. PLoS ONE 8:e Liu C-L, Bi H-R, Bai Z et al Engineering and manipulation of a mevalonate pathway in Escherichia coli for isoprene production.

Lohman DC, Aydin D, Von Bank HC et al An isoprene lipid-binding protein promotes eukaryotic coenzyme Q biosynthesis. Mol Cell. Loiseau L, Fyfe C, Aussel L et al The UbiK protein is an accessory factor necessary for bacterial ubiquinone UQ biosynthesis and forms a complex with the UQ biogenesis factor UbiJ.

Lu W, Ye L, Lv X et al Identification and elimination of metabolic bottlenecks in the quinone modification pathway for enhanced coenzyme Q 10 production in Rhodobacter sphaeroides.

Luo M, Yang X, Hu J et al The synthesis of coenzyme Q Curr Org Chem — Lv X, Xu H, Yu H Significantly enhanced production of isoprene by ordered coexpression of genes dxs , dxr , and idi in Escherichia coli. Ma Y, McClure DD, Somerville MV et al Metabolic engineering of the MEP pathway in Bacillus subtilis for increased biosynthesis of menaquinone Marbois B, Xie LX, Choi S et al para -Aminobenzoic acid is a precursor in coenzyme Q 6 biosynthesis in Saccharomyces cerevisiae.

CoQ10 is the major endogenously synthesised lipid-soluble antioxidant, protecting all types of cellular membranes from free radical-induced oxidative damage.

In addition to a role in maintaining lysosomal pH, CoQ10 also has a role in the metabolism of pyrimidines, sulphides, and amino acids. CoQ10 may also mediate the expression of a number of genes, particularly those involved in inflammation.

Given the importance of CoQ10 in normal cell functioning, it is not surprising that a deficiency of CoQ10 has been implicated in a wide range of disorders [ 2 ].

Randomised controlled trials supplementing CoQ10 in such disorders have been described, with variable success in outcomes. This in turn may be associated with a number of currently unresolved factors, such as the optimal method of administration and the ability of different tissues to take up CoQ10 once absorbed from the digestive tract [ 3 ].

Could the Bioavailability of CoQ10 Be Improved? Bioavailability is defined as the proportion of an ingested substance that reaches the bloodstream following absorption from the digestive tract.

A number of ways of improving CoQ10 bioavailability have been described; however, before addressing these, the mechanism of CoQ10 absorption must first be considered. What is known about the mechanism of CoQ10 has been described in detail with a corresponding reference list in the review by Mantle and Dybring [ 3 ] , from which the following information is derived.

Briefly, CoQ10 is absorbed via the same mechanism as any other lipid-soluble substance. Following ingestion and transit through the stomach, CoQ10 enters the duodenum where it is subject to the process of micellisation [ 3 ].

These spherical structures are small enough to diffuse between the intestinal villi, before breaking apart to release individual CoQ10 molecules adjacent to the surface of enterocyte cells responsible for CoQ10 absorption [ 3 ].

Variable dosage studies in humans have indicated that there is a finite capacity to absorb CoQ10 in a single dose [ 4 ] , suggesting that a carrier is required to facilitate the entry of CoQ10 into enterocytes.

The carrier has not been definitively identified, although the cholesterol transporter NCPC1L1 Niemann-Pick C1 Like 1 has been suggested [ 5 ] [ 6 ]. Within the enterocytes, the CoQ10 molecules are incorporated into chylomicrons. Chylomicrons are synthesised in the endoplasmic reticulum and then released from the enterocytes into the lymphatic system, from which they enter into the blood circulation.

Chylomicrons in the blood carry CoQ10 to the liver, where it is then loaded primarily into LDL low density lipoprotein and VLDL very low density lipoprotein lipoprotein particles for transport around the body [ 3 ].

Of particular importance in the absorption process outlined above is the incorporation of CoQ10 into cytosolic lipid droplets, in the initial stage of chylomicron formation within the enterocytes.

In general terms, cytosolic lipid droplets serve as a lipid storage pool during the post-prandial phase [ 7 ]. This retention of neutral lipids into enterocytes has been associated with the activity of liver X receptors, master regulators of cholesterol catabolism [ 8 ].

One of the functions of this process is to protect against the occurrence of hypertriglyceridemia, but this may also be responsible for the lag phase until supplemented CoQ10 is detected in the blood [ 9 ]. A number of proteins may be associated with the enterocyte lipid droplets, including CoQreducing enzymes such as cytochrome b5-reductase Cyb5R3 , which in part may explain why supplemental CoQ10 reaches the blood circulation in its reduced ubiquinol state [ 10 ].

Further research is therefore required to develop a clearer understanding of the role of cytosolic lipid droplets in CoQ10 transit within enterocytes, since this may in turn represent a rate-controlling step in CoQ10 absorption.

The single most effective method to date for improving CoQ10 bioavailability is arguably the patented CoQ10 crystal modification process used by Pharma Nord ApS in the manufacture of their ubiquinone form CoQ10 supplements [ 9 ].

CoQ10 is produced via a yeast fermentation process in the form of polymorphic crystals, which cannot be absorbed from the digestive tract. CoQ10 can be absorbed only as individual molecules, as noted above.

To be effective as a supplement, the CoQ10 crystals must therefore be dissociated first into individual CoQ10 molecules prior to absorption [ 9 ]. This modification to the CoQ10 crystalline form should remain in place throughout the shelf life of the CoQ10 preparation. The value of this process was demonstrated in the clinical study by Lopez-Lluch et al.

The bioavailability of the different formulations was quantified as the area under the curve AUC at 48 h. A second point relates to the relative bioavailability of the ubiquinone and ubiquinol forms of CoQ This clearly indicates that the modification in CoQ10 crystal morphology described above is essential to improve the capacity to access enterocytes.

The above finding is of relevance to claims that the ubiquinol form of supplemental CoQ10 is more bioavailable than the ubiquinone form. In addition, research carried out by the late Dr.

William Judy demonstrated that under conditions simulating the environ of the stomach and small intestine in vitro, supplemental ubiquinol is largely oxidised to ubiquinone prior to entry into enterocytes [ 11 ]. Furthermore, studies supplementing ubiquinol in dogs similarly showed oxidation of the latter to ubiquinone prior to enterocyte absorption, with the subsequent conversion of ubiquinone back to ubiquinol following the passage from enterocytes into the lymphatic system [ 12 ].

A third point arising from the study by Lopez-Lluch et al. The reason for this is currently unknown. However, again, the bioavailability of most of these formulations has not been compared directly with ubiquinone that has undergone crystal modification, the importance of which is demonstrated in the study by Lopez-Lluch et al.

above [ 9 ]. In addition, none of the modified forms of CoQ10 described above have been subject to an extensive evaluation of efficacy and safety in randomised controlled trials. In comparison, the efficacy and safety of the crystal-modified form of CoQ10 have been confirmed in a number of such clinical studies.

In summary, before claims for superior bioavailability of CoQ10 supplements based on novel formulations can be made, a comparison against the crystal-modified ubiquinone CoQ10 form should be carried out, using the same type of clinical study format as that described by Lopez-Lluch et al.

In addition, outstanding issues requiring further research are: i to establish the identity of the carrier responsible for transporting CoQ10 molecules from the intestinal milieu into enterocytes; and ii to develop a clearer understanding of the role of cytosolic lipid droplets in CoQ10 transit within enterocytes, since these may, in turn, represent rate-controlling steps in CoQ10 absorption.

Finally, the reason why some individuals have a low inherent capacity to absorb supplemental CoQ10 should be investigated, since the inclusion of such individuals in clinical trials could obscure trial outcomes.

Given the potential limitations of the absorption of CoQ10 from the digestive tract, the question arises as to whether CoQ10 could be administered intravenously. Given the low bioavailability of CoQ10 when administered orally as outlined above, the administration of CoQ10 via intravenous injection is an obvious alternative.

However, the potential problem with this approach is that there is no appreciable circulation of unbound CoQ10 in the blood; CoQ10 is transported in the blood bound principally to LDL- and VLDL-cholesterol, with a relatively small amount of CoQ10 associated with HDL cholesterol [ 3 ].

The question, therefore, arises whether it is necessary to bind CoQ10 to LDL- or VLDL-cholesterol prior to injection, or whether an alternative type of carrier or solubilisation method could be utilised. To date, no clinical studies were identified in which CoQ10 in any form was administered intravenously to human subjects.

A number of studies have been carried out in various animal species in which CoQ10 was administered intravenously, although no studies were identified in which CoQ10 was specifically coupled to LDL- or VLDL-cholesterol.

Studies in animal models typically use micellar or liposomal formulations of CoQ10 for intravenous injection.

Examples include the micellisation of CoQ10 using the surfactant caspofungin [ 17 ] to increase plasma and tissue CoQ10 levels; following intravenous injection in mice, the micellisation of CoQ10 using HCO polyoxyethylene hydrogenated castor oil to increase CoQ10 levels in liver tissue following intravenous injection in guinea pigs [ 18 ] ; and intravenous injection of liposomal CoQ10 to increase myocardial CoQ10 levels in rats [ 19 ].

Where these types of animal models were used to study pathological processes, intravenous injection of CoQ10 in micellar or liposomal formulations typically resulted in significant improvements in the parameters being studied. For example, in the latter study, increased levels of myocardial CoQ10 resulted in improved tolerance to subsequent ischaemic reperfusion injury.

In summary, clinical studies are required to confirm the safety of the above types of micellar or liposomal CoQ10 formulations for intravenous injection in humans together with further studies to determine the potential of CoQ10 bound to LDL- or VLDL cholesterol carriers for similar intravenous administration.

In vitro studies have demonstrated that the addition of alcoholic solutions of CoQ10 to foetal bovine serum results in the incorporation of CoQ10 principally to LDL-cholesterol Moreno Fernández-Ayala, personal communication , suggesting that perfusion of serum with CoQ10 could be a good strategy to be used in human studies.

Researchers have reviewed possible alternative routes of CoQ10 administration, including intraperitoneal, intramuscular, subcutaneous, and topical routes. In general terms, the rate of absorption is greatest for intraperitoneal injection, followed by the intramuscular and subcutaneous routes.

With regard to clinical studies, there are no listings in the medical literature relating to the administration of CoQ10 via intraperitoneal, intramuscular, or subcutaneous injection. However, a number of clinical studies have described the topical application of CoQ10 to the skin, the gums, or the surface of the eyes.

With regard to skin, topical application of a cream containing uM CoQ10 over a 2-week period resulted in a significant increase in CoQ10 levels in the outermost layer of the skin [ 20 ] , where it helped improve skin elasticity and reduce photoaging and wrinkle formation [ 21 ].

Topical application over a four-to-six-week period of various proprietary CoQ10 formulations to the gums of patients with periodontal disease resulted in a significant improvement in plaque index, gingival index, gingival bleeding index, and probing pocket depth, compared to scaling and planing only [ 22 ] [ 23 ] [ 24 ].

Topical application of CoQ10 in the form of proprietary eye drops has been used to improve healing in corneal ulcers [ 25 ] and to improve visual function in glaucoma patients [ 26 ]. This, in turn, is a reflection of the common use of this route to administer test substances in animals, particularly rats and mice, because of the rapidity of absorption.

The intramuscular injection of CoQ10 has been described in several animal models. Intramuscular injection of CoQ10 emulsified with ethanol was used in an investigation into lymphocyte energy metabolism in tumour-bearing rats [ 32 ].

In summary, data from the above studies provide evidence for the effective action of CoQ10 when administered by intraperitoneal, intramuscular, or subcutaneous routes in the various animal models of disease. The potential beneficial action of CoQ10 resulting from these administration routes in human subjects is an area for future research.

References Crane, F. Biochemical functions of coenzyme Q Hargreaves, I. Disorders of human coenzyme Q10 metabolism: An overview. Bioavailability of coenzyme Q An overview of the absorption process and subsequent metabolism.

Antioxidants , 9, Singh, R. Effect on absorption and oxidative stress of different oral Coenzyme Q10 dosages and intake strategy in healthy men. BioFactors , 25, — Sahoo, S. Membrane transporters in a human genome-scale metabolic knowledgebase and their implications for disease.

Takekawa, Y. An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components via Niemann—Pick C1-Like 1. Beilstein, F. Characteristics and functions of lipid droplets and associated proteins in enterocytes.

Cell Res. Cruz-Garcia, L. Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids. López-Lluch, G. Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization.

Nutrition , 57, — Characterization of the proteome of cytoplasmic lipid droplets in mouse enterocytes after a dietary fat challenge. PLoS ONE , 10, e Judy, W. The instability of the lipid-soluble antioxidant ubiquinol: Part 1-lab studies.

Encinitas , 20, 24— The instability of the lipid-soluble antioxidant ubiquinol: Part 2-dog studies. Encinitas , 20, 26— Ozcan, L. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity.

Cell Metabolism 15 , — Park, S. Proceedings of the National Academy of Sciences of USA , — Article ADS CAS Google Scholar. Cell Metabolism 18 , — Puigserver, P. Peroxisome proliferator-activated receptor-γ coactivator 1α PGC-1α : transcriptional coactivator and metabolic regulator. Endocrine Reviews 24 , 78—90 Liang, H.

PGC-1α: a key regulator of energy metabolism. Advances in Physiology Education 30 , — Article PubMed Google Scholar. Wright, D. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1α expression.

Journal of Biological Chemistry , — Lehman, J. The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis. American Journal of Physiology-Heart and Circulatory Physiology , H—H Lagouge, M.

Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell , — Lira, V. PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity.

American Journal of Physiology-Endocrinology and Metabolism , E—E CAS PubMed PubMed Central Google Scholar. Chalkiadaki, A. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nature Reviews. Endocrinology 8 , — Pfluger, P. Sirt1 protects against high-fat diet-induced metabolic damage.

Colak, Y. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Medical Science Monitor 17 , HY5—HY9 Article ADS PubMed PubMed Central Google Scholar.

Liang, F. SIRT1 and insulin resistance. Endocrinology 5 , — High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction.

Cell Metabolism 16 , — Costa Cdos, S. SIRT1 transcription is decreased in visceral adipose tissue of morbidly obese patients with severe hepatic steatosis. Obesity Surgery 20 , — Banks, A. SirT1 gain of function increases energy efficiency and prevents diabetes in mice.

Cell Metabolism 8 , — Lenaz, G. The function of coenzyme Q in mitochondria. Journal of Molecular Medicine 71 , S66—S70 CAS Google Scholar. Quinone specificity of complex I. Biochimica et Biophysica Acta BBA -Bioenergetics , — Article CAS Google Scholar.

Kalén, A. Age-related changes in the lipid compositions of rat and human tissues. Lipids 24 , — Yang, Y. Coenzyme Q10 treatment of cardiovascular disorders of ageing including heart failure, hypertension and endothelial dysfunction. Clinica Chimica Acta , 83—89 Safarinejad, M.

Effects of the reduced form of coenzyme Q10 ubiquinol on semen parameters in men with idiopathic infertility: a double-blind, placebo controlled, randomized study.

The Journal of Urology , — Toyama, K. Rosuvastatin combined with regular exercise preserves coenzyme Q10 levels associated with a significant increase in high-density lipoprotein cholesterol in patients with coronary artery disease. Atherosclerosis , — Someya, S. Tomasetti, M.

Coenzyme Q10 enrichment decreases oxidative DNA damage in human lymphocytes. Free Radical Biology and Medicine 27 , — Miyamae, T. Increased oxidative stress and coenzyme Q10 deficiency in juvenile fibromyalgia: amelioration of hypercholesterolemia and fatigue by ubiquinol supplementation.

Redox Report 18 , 12—19 Schmelzer, C. Micronutrient special issue: Coenzyme Q10 requirements for DNA damage prevention. Tian, G. Ubiquinol supplementation activates mitochondria functions to decelerate senescence in senescence-accelerated mice.

Bour, S. Coenzyme Q as an antiadipogenic factor. Lee, S. Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARα induction in 3T3-L1 preadipocytes. Cellular Signalling 24 , — Himms-Hagen, J. Thermogenesis in brown adipose tissue as an energy buffer: implications for obesity.

New England Journal of Medicine , — Nguyen, P. Liver lipid metabolism. Journal of Animal Physiology and Animal Nutrition 92 , — Cantó, C.

Li, Y. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metabolism 13 , — Gerhart-Hines et al. Molecular Cell 44 , — Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.

Bender, A. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacological Reviews 58 , — Angel, P. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation.

Biochimica et Biophysica Acta BBA -Reviews on Cancer , — Kolch, W. Biochemical Journal , — Roux, P. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiology and Molecular Biology Reviews 68, Goetze, S.

Atherosclerosis , 93— Cipolletta, E. Calmodulin-dependent kinase II mediates vascular smooth muscle cell proliferation and is potentiated by extracellular signal regulated kinase.

Endocrinology , — Grenier-Larouche et al. Omental adipocyte hypertrophy relates to coenzyme Q10 redox state and lipid peroxidation in obese women. Journal of Lipid Research 56 , — Iwatsuka, H. General survey of diabetic features of yellow KK mice.

Endocrinologia Japonica 17 , 23—35 Ventura-Clapier, R. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1α. Cardiovascular Research 79 , — Gerhart-Hines, Z. The EMBO Journal 26 , — Carling, D.

A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Letters , — Salminen, A. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan.

Journal of Molecular Medicine 89 , — Steinberg, G. AMPK in health and disease. Physiological Reviews 89 , — Ruderman, N. AMPK and SIRT1: a long-standing partnership?

Guarente, L. Sirtuins in aging and disease. In Cold Spring Harbor Symposia on Quantitative Biology Cold Spring Harbor Laboratory Press , pp. Houtkooper, R. Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology 13 , — Picard, F. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ.

Arruda, A. Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes. Cell Metabolism 22 , — Chang, Y.

Coenzyme Q10 inhibits the release of glutamate in rat cerebrocortical nerve terminals by suppression of voltage-dependent calcium influx and mitogen-activated protein kinase signaling pathway. Journal of Agricultural and Food Chemistry 60 , — Durán-Prado, M. Coenzyme Q10 protects human endothelial cells from β-amyloid uptake and oxidative stress-induced injury.

PloS One 9 , e Download references. We thank the Kaneka Corporation of Japan for providing the mouse feed.

We also thank Drs. Kiyoshi Matsumoto and Takahiro Yoshizawa Research Center for Support to Advanced Science, Shinshu University for technical assistance and care of mice.

We thank Mr. Kiyokazu Kametani and Ms. Kayo Suzuki Research Center for Support to Advanced Science, Shinshu University for their skillful technical assistance. Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, , Japan.

Department of Advanced Medicine for Heath Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, , Japan. Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, , Japan.

You can also search for this author in PubMed Google Scholar. conceived and designed experiments. and J. performed the experiments. analyzed the data.

and H. contributed reagents and materials. wrote the paper. Correspondence to Zhe Xu. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.

Reprints and permissions. Xu, Z. Coenzyme Q10 Improves Lipid Metabolism and Ameliorates Obesity by Regulating CaMKII-Mediated PDE4 Inhibition. Sci Rep 7 , Download citation.

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nature scientific reports articles article. Download PDF. Subjects Cell signalling Metabolic disorders. Abstract Our recent studies revealed that supplementation with the reduced form of coenzyme Q10 CoQ 10 H 2 inhibits oxidative stress and slows the process of aging in senescence-accelerated mice.

Introduction Imbalance between energy input and output can lead to the accumulation of excess fat, causing obesity. Results CoQ 10 H 2 inhibited weight gain and improved metabolic syndrome in KKAy mice In this study, dietary supplementation with CoQ 10 H 2 was employed to investigate the effect of CoQ 10 H 2 on metabolic syndrome in KKAy mice.

Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Figure 5. Discussion It is well known that CoQ 10 H 2 is a powerful antioxidant that can potently inhibit the generation of oxygen free radicals and oxidative stress damage, thereby ameliorating age-associated disease.

Figure 6. Methods Animals 7-week-old female KKAy mice were purchased from CLEA Japan Inc. Cell Culture The human hepatoma HepG2 cell line was provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan, and 3T3L1 cells were purchased from the Japanese Cancer Research Resources Bank.

Western blotting and immunoprecipitation Tissues and cells were lysed in cell lysis buffer Cell Signaling Technology, MA supplemented with protease inhibitors Sigma Aldrich, MO. Real-time RT-PCR Total RNA was extracted using TRIzol Reagent Invitrogen, CA , followed by treatment with DNA-Free Applied Biosystems, CA to remove contaminating DNA and then subjected to reverse transcription using an Omniscript RT kit Applied Biosystems, CA with random primers Applied Biosystems, CA.

References Kopelman, P. CAS PubMed Google Scholar Kahn, S. Article ADS CAS PubMed Google Scholar Barrett-connor, E. Article CAS PubMed Google Scholar Kratz, M.

Article CAS PubMed Google Scholar Wahba, I. Article CAS PubMed Google Scholar Furukawa, S. Article CAS PubMed PubMed Central Google Scholar Keaney, J. Article CAS PubMed Google Scholar Özcan, U. Article ADS PubMed Google Scholar Fu, S. Article ADS CAS PubMed PubMed Central Google Scholar Mantena, S.

Article CAS PubMed PubMed Central Google Scholar Bournat, J. Article CAS PubMed PubMed Central Google Scholar Matsuoka, T. Article CAS PubMed PubMed Central Google Scholar Rahmouni, K. Article CAS PubMed PubMed Central Google Scholar Ohara, Y. Article CAS PubMed PubMed Central Google Scholar Berridge, M.

Article CAS PubMed Google Scholar Ozcan, L. Article CAS PubMed PubMed Central Google Scholar Park, S. Article ADS CAS Google Scholar Ozcan, L.

Article CAS PubMed Google Scholar Puigserver, P. Article CAS PubMed Google Scholar Liang, H. Article PubMed Google Scholar Wright, D. Article CAS PubMed Google Scholar Lehman, J. Article CAS PubMed PubMed Central Google Scholar Lagouge, M.

Article CAS PubMed Google Scholar Lira, V. CAS PubMed PubMed Central Google Scholar Chalkiadaki, A. CAS PubMed Google Scholar Pfluger, P. Article ADS CAS Google Scholar Colak, Y. Article ADS PubMed PubMed Central Google Scholar Liang, F. CAS PubMed Google Scholar Chalkiadaki, A.

Article CAS PubMed PubMed Central Google Scholar Costa Cdos, S. Article PubMed Google Scholar Banks, A. Article CAS PubMed PubMed Central Google Scholar Lenaz, G. CAS Google Scholar Lenaz, G. Article CAS Google Scholar Kalén, A. Article PubMed Google Scholar Yang, Y. Article CAS Google Scholar Safarinejad, M.

Article CAS PubMed Google Scholar Toyama, K. Article CAS PubMed Google Scholar Someya, S. Article ADS CAS Google Scholar Tomasetti, M. Article CAS PubMed Google Scholar Miyamae, T.

Article CAS PubMed Google Scholar Schmelzer, C. Article CAS PubMed Google Scholar Tian, G. Article CAS Google Scholar Bour, S. Article CAS Google Scholar Lee, S. Article CAS PubMed Google Scholar Himms-Hagen, J.