Coenzyme Q10 (CoQ10; synonym: ubiquinone) is a vitaminoid (vitamin-like substance) discovered in 1957 at the University of Wisconsin. The elucidation of its chemical structure was carried out one year later by the working group led by the natural products chemist Prof. K. Folkers. Coenzymes Q are compounds of oxygen (O2), hydrogen (H) and carbon (C) atoms that form a so-called ring-shaped quinone structure. A lipophilic (fat-soluble) isoprenoid side chain is attached to the benzoquinone ring. The chemical name of coenzyme Q is 2,3-dimethoxy-5-methyl-6-polyisoprene-parabenzoquinone. Depending on the number of isoprene units, coenzymes Q1-Q10 can be distinguished, all of which occur naturally. For example, coenzyme Q9 is required by plants for photosynthesis. For humans, only coenzyme Q10 is essential. Since coenzymes Q are present in all cells – human, animal, plant, bacteria – they are also called ubiquinones (Latin “ubique” = “everywhere”). Animal foods, such as muscle meat, liver, fish, and eggs, contain mainly coenzyme Q10, while foods of plant origin have predominantly ubiquinones with a lower number of isoprene units – for example, a high amount of coenzyme Q9 is found in whole grain products. Ubiquinones have structural similarities to vitamin E and vitamin K.
Synthesis
The human organism is able to synthesize coenzyme Q10 in almost all tissues and organs. The main sites of synthesis are the membranes of mitochondria (“energy power plants” of eukaryotic cells) in the liver. The precursor for the benzoquinone moiety is the amino acid tyrosine, which is synthesized endogenously (in the body) from the essential (vital) amino acid phenylalanine. The methyl (CH3) groups attached to the quinone ring are derived from the universal methyl group donor (donating CH3 groups) S-adenosylmethionine (SAM). The synthesis of the isoprenoid side chain follows the general biosynthetic pathway of isoprenoid substances via mevalonic acid (branched-chain, saturated hydroxy fatty acid) – so-called mevalonate pathway (formation of isoprenoids from acetyl-coenzyme A (acetyl-CoA)). Coenzyme Q10 self-synthesis also requires various B-group vitamins, such as niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), folic acid (vitamin B9), and cobalamin (vitamin B12). For example, pantothenic acid is involved in the provision of acetyl-CoA, pyridoxine in the biosynthesis of benzoquinone from tyrosine and folic acid, and cobalamin in the remethylation (transfer of a CH3 group) of homocysteine to methionine (→ synthesis of SAM). An insufficient supply of the ubiquinone precursors tyrosine, SAM, and mevalonic acid and vitamins B3, B5, B6, B9, and B12 can significantly reduce endogenous Q10 synthesis and increase the risk of coenzyme Q10 deficiency. Similarly, deficient (inadequate) intake of vitamin E can reduce the self-synthesis of Q10 and lead to a significant decrease in organ ubiquinone levels. Patients on long-term total parenteral nutrition (artificial nutrition bypassing the gastrointestinal tract) often exhibit coenzyme Q10 deficiency due to insufficient endogenous (endogenous) synthesis. The reason for the deficient Q10 self-synthesis is the absence of first-pass metabolism (conversion of a substance during its first passage through the liver) from phenylalanine to tyrosine and the preferential use of tyrosine for protein biosynthesis (endogenous production of protein). In addition, the first-pass effect of methionine to SAM is absent, so that methionine is primarily transaminated to sulfate (displacement or release of an amino (NH2) group) outside the liver. In the course of diseases such as phenylketonuria (PKU), the Q10 synthesis rate can also be reduced. This disease is the most common inborn error of metabolism with an incidence (number of new cases) of about 1:8,000. Affected patients show a lack of or reduced activity of the enzyme phenylalanine hydroxylase (PAH), which is responsible for the breakdown of phenylalanine to tyrosine. The result is an accumulation (build-up) of phenylalanine in the body, leading to impaired brain development.Due to the lack of a metabolic pathway to tyrosine, a relative deficiency of this amino acid occurs, which, in addition to the biosynthesis of the neurotransmitter dopamine, the thyroid hormone thyroxine and the pigmentary pigment melanin, reduces the synthesis of coenzyme Q10. Therapy with statins (drugs used to lower cholesterol levels), which is used for hypercholesterolemia (elevated serum cholesterol levels), is associated with increased coenzyme Q10 requirements. Statins, such as simvastatin, pravastatin, lovastatin and atorvastatin, belong to the pharmacological substance class of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors, which inhibit (inhibit) the conversion of HMG-CoA to mevalonic acid – a rate-determining step in cholesterol synthesis – by blocking the enzyme. Statins are therefore also known as cholesterol synthesis enzyme (CSE) inhibitors. Via blockade of HMG-CoA reductase, which leads to decreased provision of mevalonic acid, statins prevent endogenous ubiquinone synthesis in addition to cholesterol biosynthesis. Reduced serum Q10 concentrations are often observed in patients treated with CSE inhibitors. However, it is unclear whether the decreased serum Q10 results from decreased self-synthesis or from statin-induced decrease in serum lipid levels or both, because the serum concentration of ubiquinone-10, which is transported in the blood by lipoproteins, correlates with that of circulating lipids in the blood. The impaired self-synthesis of Q10 using statins combined with low alimentary (dietary) Q10 intake increases the risk of coenzyme Q10 deficiency. For this reason, patients who need to take HMG-CoA reductase inhibitors regularly should ensure adequate dietary coenzyme Q10 intake or receive additional Q10 supplementation. The use of coenzyme Q10 can significantly reduce the side effects of CSE inhibitors, as these are partly due to a deficit of ubiquinone-10. With increasing age, a decreasing Q10 concentration can be observed in various organs and tissues. Among other things, a reduced self-synthesis is discussed as the cause, which presumably results from an insufficient supply with the ubiquinone precursors and/or with various vitamins of the B group. Thus, hyperhomocysteinemia (elevated homocysteine level) is frequently found in seniors as a result of a deficiency of vitamin B12, folic acid, and vitamin B6, respectively, which is associated with a reduced provision of SAM.
Absorption
Similar to fat-soluble vitamins A, D, E, and K, coenzymes Q are also absorbed (taken up) in the upper small intestine during fat digestion because of their lipophilic isoprenoid side chain, ie. the presence of dietary fats as a means of transporting the lipophilic molecules, of bile acids to solubilize (increase solubility) and form micelles (form transport beads that make fat-soluble substances transportable in aqueous solution), and of pancreatic esterases (digestive enzymes from the pancreas) to cleave bound ubiquinones is necessary for optimal intestinal absorption (uptake via the intestine). Food-bound ubiquinones first undergo hydrolysis (cleavage by reaction with water) in the intestinal lumen by means of esterases (digestive enzymes) from the pancreas. The coenzymes Q released in this process reach the brush border membrane of the enterocytes (cells of the small intestinal epithelium) as part of the mixed micelles (aggregates of bile salts and amphiphilic lipids) and are internalized (taken up into the cells). Intracellularly (within the cells), incorporation (uptake) of ubiquinones occurs into chylomicrons (lipid-rich lipoproteins), which transport the lipophilic vitaminoids via the lymph into the peripheral blood circulation. Due to the high molecular weight and lipid solubility, the bioavailability of the supplied ubiquinones is low and probably ranges from 5-10%. The absorption rate decreases with increasing dose. The simultaneous intake of fats and secondary plant compounds, such as flavonoids, increases the bioavailability of coenzyme Q10.
Transport and distribution in the body
During transport to the liver, free fatty acids (FFS) and monoglycerides from chylomicrons are released to peripheral tissues, such as adipose tissue and muscle, under the action of lipoprotein lipase (LPL), which is located on cell surfaces and cleaves triglycerides. This process degrades chylomicrons to chylomicron remnants (low-fat chylomicron remnants), which bind to specific receptors in the liver. Uptake of coenzymes Q into the liver occurs by receptor-mediated endocytosis (uptake into cells by invagination of the biomembrane to form vesicles). In the liver, alimentary supplied low-chain coenzymes (coenzymes Q1-Q9) are converted into coenzyme Q10. Ubiquinone-10 is subsequently stored in VLDL (very low density lipoproteins). VLDL is secreted (secreted) by the liver and introduced into the bloodstream to distribute coenzyme Q10 to extrahepatic (outside the liver) tissues. Coenzyme Q10 is localized in membranes and lipophilic subcellular structures, especially the inner mitochondrial membrane, of all body cells – primarily those with high energy turnover. The highest Q10 concentrations are found in the heart, liver, and lungs, followed by kidneys, pancreas (pancreas), and spleen. Depending on the respective redox ratios (reduction/oxidation ratios), the vitaminoid is present in oxidized (ubiquinone-10, abbreviated as CoQ10) or reduced form (ubiquinol-10, ubihydroquinone-10, abbreviated as CoQ10H2) and thus influences both the structure and the enzymatic equipment of cell membranes. For example, the activity of transmembrane phospholipases (enzymes that cleave phospholipids and other lipophilic substances) is controlled by redox status. Uptake of coenzyme Q10 by target cells is tightly coupled to lipoprotein catabolism (degradation of lipoproteins). As VLDL binds to peripheral cells, some Q10, free fatty acids, and monoglycerides are internalized (taken up into cells) by passive diffusion through the action of lipoprotein lipase. This results in the catabolism of VLDL to IDL (intermediate density lipoproteins) and subsequently to LDL (low density lipoproteins; cholesterol-rich low density lipoproteins). Ubiquinone-10 bound to LDL is taken up into liver and extrahepatic tissues via receptor-mediated endocytosis on the one hand and transferred to HDL (high density lipoproteins) on the other. HDL is significantly involved in the transport of lipophilic substances from peripheral cells back to the liver. The total ubiquinone-10 stock in the human body is supply-dependent and is thought to be 0.5-1.5 g. In various diseases or processes, such as myocardial and tumor diseases, diabetes mellitus, neurodegenerative diseases, radiation exposure, chronic stress and increasing age or risk factors, such as smoking and UV radiation, the coenzyme Q10 concentration in blood plasma, organs and tissues, such as skin, may be reduced. Free radicals or pathophysiological conditions are discussed as the cause. It remains unclear whether the reduced Q10 content itself has pathogenic effects or is merely a side effect. Decreased whole-body ubiquinone-10 with age is most noticeable in cardiac muscle, in addition to liver and skeletal muscle. While 40-year-olds have about 30% less Q10 in cardiac muscle than healthy 20-year-olds, the Q10 concentration of 80-year-olds is 50-60% lower than that of healthy 20-year-olds. Functional disorders are to be expected at a Q10 deficit of 25%, and life-threatening disorders at a drop in Q10 concentration above 75%. Several factors can be considered as the cause of a decrease in ubiquinone-10 content in old age. In addition to decreased endogenous synthesis and inadequate dietary intake, a decrease in mitochondrial mass and increased consumption due to oxidative stress appear to play a role.
