| Coenzyme Q10
| CAS number
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| Molar mass
|| 863.34 g mol−1
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Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
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Coenzyme Q10, also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQ10 //, CoQ, or Q10 is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the number of isoprenyl chemical subunits in its tail.
This oil-soluble, vitamin-like substance is present in most eukaryotic cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, generating energy in the form of ATP. Ninety-five percent of the human body’s energy is generated this way. Therefore, those organs with the highest energy requirements—such as the heart, liver and kidney—have the highest CoQ10 concentrations. There are three redox states of CoQ10: fully oxidized (ubiquinone), semiquinone (ubisemiquinone), and fully reduced (ubiquinol). The capacity of this molecule to exist in a completely oxidized form and a completely reduced form enables it to perform its functions in the electron transport chain and as an antioxidant respectively.
Discovery and history
CoQ10 was first discovered by Professor Fredrick L. Crane and colleagues at the University of Wisconsin–Madison Enzyme Institute in 1957. In 1958, its chemical structure was reported by Dr. Karl Folkers and coworkers at Merck. In 1961 Peter Mitchell proposed the electron transport chain (which includes the vital protonmotive role of CoQ10) and he received a Nobel prize for the same in 1978. In 1972, Gian Paolo Littarru and Karl Folkers separately demonstrated a deficiency of CoQ10 in human heart disease. The 1980s witnessed a steep rise in the number of clinical trials due to the availability of large quantities of pure CoQ10 and methods to measure plasma and blood CoQ10 concentrations. The redox functions of CoQ in cellular energy production and antioxidant protection are based on the ability to exchange two electrons in a redox cycle between ubiquinol (reduced CoQ) and oxidized CoQ (ubiquinone).
The antioxidant role of the molecule as a free radical scavenger was widely studied by Lars Ernster. Numerous scientists around the globe started studies on this molecule since then in relation to various diseases including cardiovascular diseases and cancer.
The oxidized structure of CoQ10
is shown on the top-right. The various kinds of Coenzyme Q can be distinguished by the number of isoprenoid subunits in their
CoQ10 is found in the membranes of many organelles. Since its primary function in cells is in generating energy, the highest concentration is found on the inner membrane of the mitochondrion. Some other organelles that contain CoQ10 include endoplasmic reticulum, peroxisomes, lysosomes, and vesicles.
CoQ10 and electron transport chain
CoQ10 is fat-soluble and is therefore mobile in cellular membranes; it plays a unique role in the electron transport chain (ETC). In the inner mitochondrial membrane, electrons from NADH and succinate pass through the ETC to oxygen, which is reduced to water. The transfer of electrons through ETC results in the pumping of H+ across the membrane creating a proton gradient across the membrane, which is used by ATP synthase (located on the membrane) to generate ATP. CoQ10 functions as an electron carrier from enzyme complex I and enzyme complex II to complex III in this process. This is crucial in the process, since no other molecule can perform this function (Note: recent research now establishes that Vitamin K2 co-performs this role with CoQ10). Thus, CoQ10 functions in every cell of the body to synthesize energy.
Antioxidant function of CoQ10
The antioxidant nature of CoQ10 derives from its energy carrier function. As an energy carrier, the CoQ10 molecule continuously goes through oxidation-reduction cycle. As it accepts electrons, it becomes reduced. As it gives up electrons, it becomes oxidized. In its reduced form, the CoQ10 molecule holds electrons rather loosely, so this CoQ molecule will quite easily give up one or both electrons and, thus, act as an antioxidant. CoQ10 inhibits lipid peroxidation by preventing the production of lipid peroxyl radicals (LOO). Moreover, CoQH2 reduces the initial perferryl radical and singlet oxygen, with concomitant formation of ubisemiquinone and H2O2. This quenching of the initiating perferryl radicals, which prevent propagation of lipid peroxidation, protects not only lipids, but also proteins from oxidation. In addition, the reduced form of CoQ effectively regenerates vitamin E from the a-tocopheroxyl radical, thereby interfering with the propagation step. Furthermore, during oxidative stress, interaction of H2O2 with metal ions bound to DNA generates hydroxyl radicals and CoQ efficiently prevents the oxidation of bases, in particular, in mitochondrial DNA. In contrast to other antioxidants, this compound inhibits both the initiation and the propagation of lipid and protein oxidation. It also regenerates other antioxidants such as vitamin E. The circulating CoQ10 in LDL prevents oxidation of LDL, which may provide benefit in cardiovascular diseases.
Starting from acetyl-CoA, a multistep process of mevalonate pathway produces farnesyl-PP (FPP), the precursor for cholesterol, CoQ, dolichol, and isoprenylated proteins. An important enzyme in this pathway is HMG Co-A reductase, which is usually a target for intervention in cardiovascular complications. The "statin" family of cholesterol reducing medications block HMG Co-A reductase, so taking CoQ10 may alleviate a statin side effect of rhabdomyolysis. The long isoprenoid side-chain of CoQ is synthesized by trans-prenyltransferase, which condenses FPP with several molecules of isopentenyl-PP (IPP), all in the trans configuration. The next step involves condensation of this polyisoprenoid side-chain with 4-hydroxybenzoate, catalyzed by polyprenyl-4-hydroxy benzoate transferase. Hydroxybenzoate is synthesized from tyrosine or phenylalanine. In addition to their presence in mitochondria, these initial two reactions also occur in the endoplasmic reticulum and peroxisomes, indicating multiple sites of synthesis in animal cells. Increasing the endogenous biosynthesis of CoQ10 has attained attention in the recent years as a strategy to fight CoQ10 deficiency.
Genes involved include PDSS1, PDSS2, COQ2, and COQ8/CABC1.
Absorption and metabolism
CoQ10 is a crystalline powder that is insoluble in water. Absorption follows the same process as that of lipids and the uptake mechanism appears to be similar to that of vitamin E, another lipid-soluble nutrient. This process in the human body involves the secretion into the small intestines of pancreatic enzymes and bile that facilitate emulsification and micelle formation that is required for the absorption of lipophilic substances. Food intake (and the presence of lipids) stimulates bodily biliary excretion of bile acids and greatly enhances the absorption of CoQ10. Exogenous CoQ10 is absorbed from the small intestinal tract and is best absorbed if it is taken with a meal. Serum concentration of CoQ10 in fed condition is higher than in fasting conditions.
Data on the metabolism of CoQ10 in animals and humans are limited. A study with 14C-labeled CoQ10 in rats showed most of the radioactivity in the liver 2 hours after oral administration when the peak plasma radioactivity was observed, but it should be noted that CoQ9 is the predominant form of coenzyme Q in rats. It appears that CoQ10 is metabolised in all tissues, while a major route for its elimination is biliary and fecal excretion. After the withdrawal of CoQ10 supplementation, the levels return to normal within a few days, irrespective of the type of formulation used.
CoQ10 deficiency and toxicity
There are two major factors that lead to deficiency of CoQ10 in humans: reduced biosynthesis, and increased utilization by the body. Biosynthesis is the major source of CoQ10. Biosynthesis requires at least 12 genes, and mutations in many of them cause CoQ deficiency. CoQ10 levels can also be affected by other genetic defects (such as mutations of mitochondrial RNA, ETFDH, APTX and BRAF, genes that are not directly related to the CoQ10 biosynthetic process) while the role of statins is controversial. Some chronic disease conditions (cancer, heart disease, etc.) are also thought to reduce the biosynthesis and increase the demand for CoQ10 in the body, but there are no definite data to support these claims.
Toxicity is not usually observed with high doses of CoQ10. A daily dosage up to 3600 mg was found to be tolerated by healthy as well as unhealthy persons. However, some adverse effects, largely gastrointestinal, are reported with very high intakes. The observed safe level (OSL) risk assessment method indicated that the evidence of safety is strong at intakes up to 1200 mg/day, and this level is identified as the OSL.
Clinical assessment techniques
Although CoQ10 can be measured in plasma, these measurements reflect dietary intake rather than tissue status. Currently, most clinical centers measure CoQ10 levels in cultured skin fibroblasts, muscle biopsies, and in blood mononuclear cells.
Culture fibroblasts can be used also to evaluate the rate of endogenous CoQ10 biosynthesis, by measuring the uptake of 14C-labelled p-hydroxybenzoate.
Inhibition by statins and beta blockers
CoQ10 shares a biosynthetic pathway with cholesterol. The synthesis of an intermediary precursor of CoQ10, mevalonate, is inhibited by some beta blockers, blood pressure-lowering medication, and statins, a class of cholesterol-lowering drugs. Statins can reduce serum levels of CoQ10 by up to 40%. Some research suggests the logical option of supplementation with CoQ10 as a routine adjunct to any treatment that may reduce endogenous production of CoQ10, based on a balance of likely benefit against very small risk. However, there are still no conclusive data that support the role of CoQ10 deficiency in the pathogenesis of statin-related myopathy.
Some reports have been published on the pharmacokinetics of CoQ10. The plasma peak can be observed 2–6 hours after oral administration, mainly depending on the design of the study. In some studies, a second plasma peak was also observed at about 24 hours after administration, probably due to both enterohepatic recycling and redistribution from the liver to circulation. Tomono et al. used deuterium-labelled crystalline CoQ10 to investigate pharmacokinetics in human and determined an elimination half-time of 33 hours.
Improving the bioavailability of CoQ10
The importance of how drugs are formulated for bioavailability is well known. In order to find a principle to boost the bioavailability of CoQ10 after oral administration, several new approaches have been taken; different formulations and forms have been developed and tested on animals or humans.
Reduction of particle size
An obvious strategy is reduction of the particle size to as low as the micro- and nano-scale. Nanoparticles have been explored as a delivery system for various drugs and an improvement of the oral bioavailability of drugs with poor absorption characteristics has been reported; the pathways of absorption and the efficiency were affected by reduction of particle size. This protocol has so far not proved to be very successful with CoQ10, although reports have differed widely. The use of the aqueous suspension of finely powdered CoQ10 in pure water has also revealed only a minor effect.
Soft-gel capsules with CoQ10 in oil suspension
A successful approach was 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 utilised in the preparation of soft gelatine capsules. In one of the first such attempts, Ozawa et al. performed a pharmacokinetic study on beagle dogs in which the emulsion of CoQ10 in soybean oil was investigated; about two times higher plasma CoQ10 level than that of the control tablet preparation was determined during administration of a lipid microsphere. Although an almost negligible improvement of bioavailability was observed by Kommuru et al. with oil-based soft-gel capsules in a later study on dogs, the significantly increased bioavailability of CoQ10 was confirmed for several oil-based formulations in most other studies.
Novel forms of CoQ10 with increased water-solubility
Facilitating drug absorption by increasing its solubility in water is a common pharmaceutical strategy and has also been shown to be successful for CoQ10. Various approaches have been developed to achieve this goal, with many of them producing significantly better results over oil-based soft-gel capsules in spite of the many attempts to optimize their composition. Examples of such approaches are use of the aqueous dispersion of solid CoQ10 with tyloxapol polymer, formulations based on various solubilising agents, i.e., hydrogenated lecithin, and complexation with cyclodextrins; among the latter, complex with β-cyclodextrin has been found to have highly increased bioavailability. and is also used in pharmaceutical and food industry for CoQ10-fortification. Also some other novel carrier systems like liposomes, nanoparticles, dendrimers etc. can be used to increase the bioavailability of CoQ10.
CoQ10 has been proposed as a treatment for numerous conditions, but its medical use remains controversial. It is not approved by the FDA for the treatment of any condition, although it has been approved for further investigation (in its reduced form as solubilized ubiquinol) as an orphan product in the treatment of Huntington's disease and pediatric congestive heart failure.
Patients with congestive heart failure (CHF) have low plasma concentrations of CoQ10, which is also associated with elevated ratios of low-density lipoprotein cholesterol relative to reduced levels of high-density lipoprotein cholesterol. In one study of 236 patients with CHF, CoQ10 was an independent predictor of mortality.
CoQ10 is available as medicine and food supplement in several European countries.
Studies in the 1990s concluded that dietary supplements with CoQ10 reduced oxidation of low-density lipoprotein.
The Q-SYMBIO trial is a randomized, controlled trial to determine the benefits of CoQ10, with an endpoint including survival, with 422 patients with chronic heart failure.
Results have not yet been published, but investigators reported at the Heart Failure 2013 congress that after 2 years, patients in the CoQ10 group had half the rate of death as patients in the placebo group. Other cardiologists said this study was well-done, but was small and required confirmation. Previous recommendations on CoQ10 were that it appears to be safe, doesn't seem to have any side effects, can't hurt, but is probably not a huge benefit and is expensive.
Supplementation of CoQ10 has been found to have a beneficial effect on the condition of some sufferers of migraine headaches. A double-blind, randomized, placebo-controlled trial found statistically significant results with a small sample size of 42 patients. Dosages were 150 to 300 mg/day.
It has been used effectively in the prophylaxis of migraines, especially in combination with a daily supplement of magnesium citrate 500 mg and riboflavin (vitamin B2) 400 mg.
CoQ10 is also being investigated as a treatment for cancer, and as relief from cancer treatment side-effects.
Another recent study shows a survival benefit after cardiac arrest if CoQ10 is administered in addition to commencing active cooling of the body to 90–93 degrees Fahrenheit (32–34 degrees Celsius).
There are several reports concerning the effect of CoQ10 on blood pressure in human studies.
A recent (2007) meta-analysis of the clinical trials of CoQ10 for hypertension reviewed all published trials of CoQ10 for hypertension, and assessed overall efficacy, consistency of therapeutic action, and side-effect incidence. Meta-analysis was performed in 12 clinical trials (362 patients) comprising three randomized controlled trials, one crossover study, and eight open-label studies. The meta-analysis concluded that CoQ10 has the potential in hypertensive patients to lower systolic blood pressure by up to 17 mm Hg and diastolic blood pressure by up to 10 mm Hg without significant side-effects.
A review study has shown that there is no clinical benefit to the use of CoQ10 in the treatment of periodontal disease. Most of the studies suggesting otherwise were outdated, focused on in-vitro tests, had too few test subjects and/or erroneous statistical methodology and trial set-up, or were sponsored by a manufacturer of the product.
Dr. Bruno Loos, head of the periodontology department at Academisch Centrum Tandheelkunde Amsterdam (ACTA), states that the Pharma Nord website links to scientific articles that should prove the effectiveness of CoQ10 for periodontal disease, but all are of very poor quality. The Dutch Academy of Periodontics (NvvP) has issued numerous warnings against claims of any link between CoQ10 and periodontal disease.
One study demonstrated that low dosages of CoQ10 reduce oxidation and DNA double-strand breaks, and a combination of a diet rich in polyunsaturated fatty acids and CoQ10 supplementation leads to a longer lifespan in rats. Coles and Harris demonstrated an extension in the lifespan of rats when they were given CoQ10 supplementation. But multiple studies have since found no increase in lifespan or decrease in aging in mice and rats supplemented with CoQ10. Another study demonstrated that CoQ10 extends the lifespan of C. elegans (nematode).
In 2002, a study reported that, in rat experiments, CoQ10 taken as dietary supplement reduced radiation damage to the animals' blood.
A phase III trial of 1200 mg/d and 2400 mg/d for Parkinson's disease was discontinued early for lack of effectiveness in August 2011, and concluded, "The investigational drug is unlikely to demonstrate efficacy over placebo for this indication. However, no safety issues were discovered."
CoQ10 may be of benefit as an ingredient for topical cosmetic products.
CoQ10 concentrations in foods and dietary intake
Detailed reviews on occurrence of CoQ10 and dietary intake were published in 2010. Besides endogenous synthesis, CoQ10 is also supplied to the organism by various foods. However, despite the scientific community’s great interest in this compound, a very limited number of studies have been performed to determine the contents of CoQ10 in dietary components. The first reports on this issue were published in 1959, but the sensitivity and selectivity of the analytical methods at that time did not allow reliable analyses, especially for products with low concentrations. Developments in analytical chemistry have since enabled a more reliable determination of CoQ10 concentrations in various foods (Table below).
CoQ10 levels in selected foods
|| CoQ10 concentration [mg/kg]
||up to 10
Meat and fish are the richest source of dietary CoQ10 and levels over 50 mg/kg can be found in beef, pork, and chicken heart, and in chicken liver. Dairy products are much poorer sources of CoQ10 compared to animal tissues. Vegetable oils are also quite rich in CoQ10. Within vegetables, parsley, and perilla are the richest CoQ10 sources, but significant differences in their CoQ10 levels can be found in the literature. Broccoli, grape, and cauliflower are modest sources of CoQ10. Most fruit and berries represent a poor to very poor source of CoQ10, with the exception of avocado, with a relatively high CoQ10 content.
In the developed world, the estimated daily intake of CoQ10 has been determined at 3–6 mg per day, derived primarily from meat.
Effect of heat and processing
Cooking by frying reduces CoQ10 content by 14–32%.
- Idebenone – synthetic analog with reduced oxidant generating properties
- Huntington's Disease Outreach Project for Education at Stanford
- Detailed discussion of coenzyme q10 health benefits
- Robert Alan Bonakdar and Erminia Guarneri,
- University of Washington
- Oregon State University
- National Institute of Neurological Disorders and Stroke
electron transport chain/