Coenzyme Q10

Biological functions

CoQ10 is a component of the mitochondrial electron transport chain (ETC), where it plays a role in oxidative phosphorylation, a process required for the biosynthesis of adenosine triphosphate, the primary energy source of cells.

CoQ10 is a lipophilic molecule that is located in all biological membranes of the human body and serves as a component for the synthesis of ATP and is a life-sustaining cofactor for the three complexes (complex I, complex II, and complex III) of the ETC in the mitochondria. CoQ10 has a role in the transport of protons across lysosomal membranes to regulate pH in lysosome functions.

The mitochondrial oxidative phosphorylation process occurs in the inner mitochondrial membrane of eukaryotic cells. This membrane is highly folded into structures called cristae, which increase the surface area available for oxidative phosphorylation. CoQ10 plays a role in this process as an essential cofactor of the ETC located in the inner mitochondrial membrane and serves the following functions:

• electron transport in the mitochondrial ETC, by shuttling electrons from mitochondrial complexes like nicotinamide adenine dinucleotide (NADH), ubiquinone reductase (complex I), and succinate ubiquinone reductase (complex II), the fatty acids and branched-chain amino acids oxidation (through flavin-linked dehydrogenases) to ubiquinol–cytochrome-c reductase (complex III) of the ETC:
• antioxidant activity as a lipid-soluble antioxidant together with vitamin E, scavenging reactive oxygen species and protecting cells against oxidative stress,

Biochemistry

Coenzyme Q (CoQ) is a quinone and functions as an electron carrier in the mitochondrial electron transport chain (ETC) of eukaryotes and many bacteria. The other name for CoQ is ubiquinone which was assigned by the IUPAC-IUB Commission on Biochemical Nomenclature in 1975 due to its ubiquitous presence from bacteria to humans. In humans the isoprene side chain has ten isoprene units, hence the abbreviation CoQ10.

Coenzymes Q is a coenzyme family that is ubiquitous in animals and many Pseudomonadota, a group of gram-negative bacteria. The fact that the coenzyme is ubiquitous gives the origin of its other name, ubiquinone. In humans, the most common form of coenzymes Q is coenzyme Q10, also called CoQ10 () or ubiquinone-10.

Coenzyme Q10 is a 1,4-benzoquinone, in which "Q" refers to the quinone chemical group and "10" refers to the number of isoprenyl chemical subunits (shown enclosed in brackets in the diagram) in its tail. In natural ubiquinones, there are from six to ten subunits in the tail, with humans having a tail of 10 isoprene units (50 carbon atoms) connected to its benzoquinone "head".

This family of fat-soluble substances is present in all respiring eukaryotic cells, primarily in the mitochondria. Organs with the highest energy requirements—such as the heart, liver, and kidney—have the highest CoQ10 concentrations.

There are three redox states of CoQ: fully oxidized (ubiquinone), semiquinone (ubisemiquinone), and fully reduced (ubiquinol). The capacity of this molecule to act as a two-electron carrier (moving between the quinone and quinol form) and a one-electron carrier (moving between the semiquinone and one of these other forms) is central to its role in the electron transport chain due to the iron–sulfur clusters that can only accept one electron at a time and as a free radical–scavenging antioxidant.

Deficiency

There are two major pathways of deficiency of CoQ10 in humans: reduced biosynthesis, and increased use by the body. Biosynthesis is the major source of CoQ10. Biosynthesis requires at least 15 genes, and mutations in any of them can cause CoQ deficiency. CoQ10 levels also may be affected by other genetic defects (such as mutations of mitochondrial DNA, ETFDH, APTX, FXN, and BRAF, genes that are not directly related to the CoQ10 biosynthetic process). Some of these, such as mutations in COQ6, can lead to serious diseases such as steroid-resistant nephrotic syndrome with sensorineural deafness.

Assessment

Although CoQ10 may be measured in blood plasma, these measurements reflect dietary intake rather than tissue status. Currently, most clinical centers measure CoQ10 levels in cultured skin fibroblasts, muscle biopsies, and blood mononuclear cells. Culture fibroblasts can be used also to evaluate the rate of endogenous CoQ10 biosynthesis, by measuring the uptake of 14C-labeled p-hydroxybenzoate.

CoQ10 is studied as an adjunctive therapy to reduce inflammation in periodontitis.

Statins

Although statins may reduce CoQ10 in the blood it is unclear if they reduce CoQ10 in muscle. Evidence does not support that supplementation improves statin side effects.

Chemical properties

The oxidized structure of CoQ10 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 CoQ10. 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 Q3. :[[File:Unibuinone3.svg|none|300px|alt=Coenzyme Q3]]

In its pure state, it is an orange-colored lipophile powder and has no taste or odor.

Biosynthesis

Biosynthesis occurs in most human tissue. There are three major steps:

1. Creation of the benzoquinone structure (using phenylalanine or tyrosine, via 4-hydroxybenzoate)
2. Creation of the isoprene side chain (using acetyl-CoA)
3. The joining or condensation of the above two structures

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 CoQ10, 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.

Genes involved include PDSS1, PDSS2, COQ2, and ADCK3 (COQ8, CABC1).

Organisms other than humans produce the benzoquinone and isoprene structures from somewhat different source chemicals. 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.

Dietary supplement

Although neither a prescription drug nor an essential nutrient, CoQ10 is commonly used as a dietary supplement with the intent to prevent or improve disease conditions, such as cardiovascular disorders. Despite its significant role in the body, it is not used as a drug to treat any specific disease.

Nevertheless, CoQ10 is widely available as an over-the-counter dietary supplement and is recommended by some healthcare professionals, despite a lack of definitive scientific evidence supporting these recommendations,

Regulation and composition

CoQ10 is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of any medical condition. However, it is sold as a dietary supplement not subject to the same regulations as medicinal drugs, and is an ingredient in some cosmetics. The manufacture of CoQ10 is not regulated, and different batches and brands may vary significantly.

Research

A 2014 Cochrane review found insufficient evidence to make a conclusion about its use for the prevention of heart disease. A 2016 Cochrane review concluded that CoQ10 had no effect on blood pressure. A 2021 Cochrane review found "no convincing evidence to support or refute" the use of CoQ10 for the treatment of heart failure.

A 2017 meta-analysis of people with heart failure taking 30–100 mg/d of CoQ10 found a 31% lower mortality and increased exercise capacity, with no significant difference in the endpoints of left heart ejection fraction. A 2021 meta-analysis found that CoQ10 was associated with a 31% lower all-cause mortality in HF patients. In a 2023 meta-analysis of older people, ubiquinone had evidence of a cardiovascular effect, but ubiquinol (the reduced form) did not.

Although CoQ10 has been studied as a potential remedy to treat purported muscle-related side effects of statin medications, the results were mixed. Although a 2018 meta-analysis concluded that there was preliminary evidence for oral CoQ10 reducing statin-associated muscle symptoms, including muscle pain, muscle weakness, muscle cramps, and muscle tiredness, 2015 and 2024 meta-analysis found that CoQ10 had no effect on statin myopathy.

Pharmacology

Absorption

CoQ10 in the pure form is a crystalline powder insoluble in water. Absorption as a pharmacological substance 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. Food intake (and the presence of lipids) stimulates bodily biliary excretion of bile acids and greatly enhances absorption of CoQ10. Exogenous CoQ10 is absorbed from the small intestine and is best absorbed if taken with a meal. Serum concentration of CoQ10 in fed condition is higher than in fasting conditions.

Metabolism

CoQ10 is metabolized in all tissues, with the metabolites phosphorylated in cells. CoQ10 is reduced to ubiquinol during or after absorption in the small intestine. It is absorbed by chylomicrons, and redistributed in the blood within lipoproteins. Its elimination occurs via biliary and fecal excretion.

Pharmacokinetics

Some reports have been published on the pharmacokinetics of CoQ10. The plasma peak can be observed 6–8 hours after oral administration when taken as a pharmacological substance. In some studies, a second plasma peak was observed approximately 24 hours after administration, probably due to enterohepatic recycling and redistribution from the liver to circulation.

Deuterium-labeled crystalline CoQ10 was used to investigate pharmacokinetics in humans to determine an elimination half-time of 33 hours.**

Bioavailability

In contrast to the intake of CoQ10 as a constituent of food, such as nuts or meat, from which CoQ10 is normally absorbed, there is a concern about CoQ10 bioavailability when it is taken as a dietary supplement. Bioavailability of CoQ10 supplements may be reduced due to the lipophilic nature of its molecule and large molecular weight.

Reduction of particle size

Nanoparticles have been explored as a delivery system for various drugs, such as improving the oral bioavailability of drugs with poor absorption characteristics. However, this has not proved successful with CoQ10, although reports have differed widely. The use of aqueous suspension of finely powdered CoQ10 in pure water also reveals only a minor effect.

Water-solubility

Facilitating drug absorption by increasing its solubility in water is a common pharmaceutical strategy and also is 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 despite the many attempts to optimize their composition. Examples of such approaches are use of the aqueous dispersion of solid CoQ10 with the polymer tyloxapol, formulations based on various solubilising agents, such as hydrogenated lecithin, and complexation with cyclodextrins; among the latter, the complex with β-cyclodextrin has been found to have highly increased bioavailability and also is used in pharmaceutical and food industries for CoQ10-fortification.

Adverse effects and precautions

Generally, oral CoQ10 supplementation is well tolerated. Some adverse effects, largely gastrointestinal, are reported with intakes.

Caution should be observed in the use of CoQ10 supplementation in people with bile duct obstruction and during pregnancy or breastfeeding.

Potential drug interactions

CoQ10 taken as a pharmacological substance has potential to inhibit the effects of theophylline as well as the anticoagulant warfarin; CoQ10 may interfere with warfarin's actions by interacting with cytochrome p450 enzymes thereby reducing the INR, a measure of blood clotting. The structure of CoQ10 is similar to that of vitamin K, which competes with and counteracts warfarin's anticoagulation effects. CoQ10 is not recommended in people taking warfarin due to the increased risk of clotting.

Dietary concentrations

Detailed reviews on occurrence of CoQ10 and dietary intake were published in 2010. Besides the endogenous synthesis within organisms, CoQ10 also is supplied by various foods. CoQ10 concentrations in various foods are:

Vegetable oils, meat, and fish are rich in CoQ10. Dairy products are much poorer sources of CoQ10 than animal tissues. Among vegetables, broccoli and cauliflower are good sources of CoQ10. Most fruits and berries are poor sources of CoQ10, except avocados, which have relatively high oil and CoQ10 content.

Intake

In the developed world, the estimated daily intake of CoQ10 has been determined at 3–6 mg per day, derived primarily from meat.

South Koreans have an estimated average daily CoQ (Q9 + Q10) intake of 11.6 mg/d, derived primarily from kimchi.

Effect of heat and processing

Cooking by frying reduces CoQ10 content by 14–32%.

History

In 1950, a small amount of CoQ10 was isolated from the lining of a horse's gut, a compound initially called substance SA, but later deemed to be quinone found in many animal tissues. In 1957, the same compound was isolated from mitochondrial membranes of beef heart, with research showing that it transported electrons within mitochondria. It was called Q-275 as a quinone. The Q-275/substance SA was later renamed ubiquinone as it was a ubiquitous quinone found in all animal tissues. In 1958, its full chemical structure was reported. Ubiquinone was later called either mitoquinone or coenzyme Q due to its participation to the mitochondrial electron transport chain. In 1966, a study reported that reduced CoQ6 was an effective antioxidant in cells.

References

References

1. (2018). "Coenzyme Q10". Micronutrient Information Center, Linus Pauling Institute, Oregon State University.
2. (30 January 2024). "Coenzyme Q10". StatPearls, US National Library of Medicine.
3. (January 2019). "Coenzyme Q10". National Center for Complementary and Integrative Health, US National Institutes of Health.
4. (January 2023). "Coenzyme Q10 Metabolism: A Review of Unresolved Issues". International Journal of Molecular Sciences.
5. (2022). "The Impact of Coenzyme Q10 on Neurodegeneration: A Comprehensive Review". Current Pharmacology Reports.
6. (May 2021). "Coenzyme Q10 and Immune Function: An Overview". Antioxidants.
7. (2024). "Understanding coenzyme Q". Physiological Reviews.
8. (September 2010). "Occurrence, biosynthesis and function of isoprenoid quinones". Biochimica et Biophysica Acta (BBA) – Bioenergetics.
9. (1989). "Human serum ubiquinol-10 levels and relationship to serum lipids". International Journal for Vitamin and Nutrition Research.
10. (June 1992). "Distribution and redox state of ubiquinones in rat and human tissues". Archives of Biochemistry and Biophysics.
11. (January 1994). "Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin". The Journal of Investigative Dermatology.
12. (2008). "Improving the bioavailability of coenzyme q10 from theory to practice". Agro Food Industry Hi-Tech.
13. (January 2015). "Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency". J Inherit Metab Dis.
14. (2011). "COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness". Journal of Clinical Investigation.
15. (2020). "''COQ6'' mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy". JIMD Reports.
16. "Nephrotic Syndrome – COQ6 Associated (Concept Id: C4054393) – MedGen – NCBI".
17. (October 2011). "Coenzyme Q deficiency in muscle". Current Opinion in Neurology.
18. (June 2008). "Analysis of coenzyme Q10 in muscle and fibroblasts for the diagnosis of CoQ₁₀ deficiency syndromes". Clinical Biochemistry.
19. (February 2024). "Can vitamins improve periodontal wound healing/regeneration?". Periodontol 2000.
20. (June 2017). "Coenzyme Q10 supplementation in the management of statin-associated myalgia". American Journal of Health-System Pharmacy.
21. (1 April 2020). "Effect of Coenzyme Q10 on statin-associated myalgia and adherence to statin therapy: A systematic review and meta-analysis". Atherosclerosis.
22. (May 2010). "Coenzyme Q—biosynthesis and functions". Biochemical and Biophysical Research Communications.
23. (2009). "Inherited Neuromuscular Diseases: Translation from Pathomechanisms to Therapies". Springer.
24. (September 2001). "Ubiquinone biosynthesis in microorganisms". FEMS Microbiology Letters.
25. (March 2020). "Coenzyme Q10 supplementation: Efficacy, safety, and formulation challenges". Comprehensive Reviews in Food Science and Food Safety.
26. (April 2022). "Coenzyme Q₁₀". [[National Cancer Institute]].
27. ((PDQ Integrative, Alternative, and Complementary Therapies Editorial Board)). (2002). "Coenzyme Q10: Health Professional Version". PDQ Integrative, Alternative, and Complementary Therapies Editorial Board.
28. (14 May 2014). "PDQ Coenzyme Q₁₀". [[National Cancer Institute]], [[National Institutes of Health]], [[United States Department of Health and Human Services.
29. (28 March 2017). "Mitochondrial disorders in children: Co-enzyme Q10". National Institute for Health and Care Excellence.
30. (May 2000). "[Coenzyme Q10—its importance, properties and use in nutrition and cosmetics]". Ceska a Slovenska Farmacie.
31. (4 December 2014). "Co-enzyme Q10 supplementation for the primary prevention of cardiovascular disease". The Cochrane Database of Systematic Reviews.
32. (March 2016). "Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension". The Cochrane Database of Systematic Reviews.
33. (February 2021). "Coenzyme Q10 for heart failure". The Cochrane Database of Systematic Reviews.
34. (July 2017). "Efficacy of CoQ₁₀ in patients with cardiac failure: a meta-analysis of clinical trials". BMC Cardiovascular Disorders.
35. (June 2021). "Dietary interventions and nutritional supplements for heart failure: a systematic appraisal and evidence map". European Journal of Heart Failure.
36. (December 2023). "Comparison of Coenzyme Q10 (Ubiquinone) and Reduced Coenzyme Q10 (Ubiquinol) as Supplement to Prevent Cardiovascular Disease and Reduce Cardiovascular Mortality". Current Cardiology Reports.
37. (October 2018). "Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials". Journal of the American Heart Association.
38. (January 2015). "Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials". Mayo Clinic Proceedings.
39. (May 2006). "Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics". Free Radical Research.
40. (1991). "Biomedical and clinical aspects of coenzyme Q".
41. (November 2010). "Improvement in intestinal coenzyme q10 absorption by food intake". Yakugaku Zasshi.
42. (October 1986). "Pharmacokinetic study of deuterium-labeled coenzyme Q10 in man". International Journal of Clinical Pharmacology, Therapy, and Toxicology.
43. (2020). "Bioavailability of Coenzyme Q10: An Overview of the Absorption Process and Subsequent Metabolism". Antioxidants.
44. (2019). "Bioavailability and Sustained Plasma Concentrations of CoQ10 in Healthy Volunteers by a Novel Oral Timed-Release Preparation". Nutrients.
45. (March 1997). "Biologically erodable microspheres as potential oral drug delivery systems". Nature.
46. (November 2010). "Preparation and characterization of novel coenzyme Q10 nanoparticles engineered from microemulsion precursors". AAPS PharmSciTech.
47. (November 2010). "Comparative bioavailability of two novel coenzyme Q10 preparations in humans". International Journal of Clinical Pharmacology and Therapeutics.
48. (April 1986). "Intestinal absorption enhancement of coenzyme Q10 with a lipid microsphere". Arzneimittel-Forschung.
49. "Particles with modified physicochemical properties, their preparation and uses".
50. "Aqueous solution containing ubidecarenone".
51. (2008). "Relative bioavailability of two forms of a novel water-soluble coenzyme Q10". Annals of Nutrition & Metabolism.
52. (2010). "A Study on the Bioavailability of a Novel Sustained-Release Coenzyme Q₁₀-β-Cyclodextrin Complex". Integrative Medicine.
53. (April 2016). "Coenzyme Q10 and Heart Failure: A State-of-the-Art Review". Circulation: Heart Failure.
54. (April 2010). "Coenzyme Q10 contents in foods and fortification strategies". Critical Reviews in Food Science and Nutrition.
55. (2011). "Ubiquinone contents in Korean fermented foods and average daily intakes". Journal of Food Composition and Analysis.
56. (1997). "The coenzyme Q10 content of the average Danish diet". International Journal for Vitamin and Nutrition Research.
57. (December 1958). "Ubiquinone". Nature.
58. (July 1957). "Isolation of a quinone from beef heart mitochondria". Biochimica et Biophysica Acta.
59. (1958). "Coenzyme Q. I. structure studies on the coenzyme Q group". Journal of the American Chemical Society.
60. (July 1966). "Quinones and quinols as inhibitors of lipid peroxidation". Lipids.