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Coenzyme Q10

Coenzyme Q10

GlossarySuccess Chemistry Staff

Coenzyme Q is a lipid  present in plants, bacteria, fungi, and all animal tissues

Coenzyme Q refers to a general structure composed of

a nucleus, that is, 2,3-dimethoxy-5-methyl benzoquinone,

and, substituted at position 6 of this quinone, a side chain

consisting of isoprene units (5 carbons), all in trans configuration

and with one double bond. In human tissues, the

major part of coenzyme Q is coenzyme Q10, which has 10

isoprene units; only 2% to 7% is present as coenzyme Q9.

NAME AND GENERAL DESCRIPTION

Coenzyme Q10 (C59H90O4) has a molecular weight of

863.3, melting point of 49◦C, and redox potential of around

+100 mV. The lipid is soluble in most organic solvents but

not in water. The term coenzyme Q refers to both oxidized

and reduced forms.

The oxidized form of coenzyme Q, ubiquinone

(CoQ), has an absorption maximum at 275 nm, whereas

its reduced form, ubiquinol (CoQH2), has a small maximum

at 290 nm. The absorption of CoQ at 210 nm is six

times higher than that at 275 nm, but absorption at 210 nm

is not specific for CoQ; this reflects the double bonds of

the polyisoprenoid moiety and is therefore unspecific. The

two major features of the lipid are the quinone moiety and

the side chain. The quinone moiety is the basis for the redox

function of this coenzyme, allowing continuous oxidation

reduction (Fig. 1) as a result of enzymatic actions.

The long polyisoprenoid side chain gives the molecule its

highly hydrophobic character and influences its physical

properties and arrangement in membranes.

 

EXTRACTION AND ANALYSIS

For analysis of the blood and tissue level of coenzyme

Q, extraction is usually performed with organic solvents

without previous acid or alkaline hydrolysis (1). The simplest

procedure is using petroleum ether, hexane, or isopropyl

alcohol and methanol. In this system, phase separation

occurs, and the methanol phase retains all the

phospholipids, which make up more than 90% of the total

lipid in most tissues. The separated neutral lipids, among

them coenzyme Q, are generally isolated and quantified

by reversed phase high-performance liquid chromatography

(HPLC) and UV detection. Both the sensitivity and

the specificity of the method can be improved greatly

by using electrochemical detection. In addition, this latter

procedure makes it possible to analyze—under certain

conditions—the ratio of oxidized/reduced coenzyme Q

amount, reflecting the in vivo situation.

 Coenzyme Q10 Biosynthesis

The biosynthesis of coenzyme Q in animal and human

tissues is unique though the initial section, designated

the mevalonate pathway, is identical for the production

of coenzyme Q, cholesterol, dolichol, and isoprenylated

proteins (2). After the branch point, however, the terminal

portions of the biosynthetic pathways for each of the

products are specific.

The mevalonate pathway consists of eight enzymatic

reactions, which lead to the production of farnesyl

pyrophosphate, the common initial substrate for

all terminal products mentioned earlier. The pathway

starts with two enzymatic steps using three molecules of

acetyl-CoA, resulting in 3-hydroxy-3-methylglutaryl-CoA

(HMG-CoA). The next reaction is a reduction to mevalonate

by HMG-CoA reductase. This reaction is considered

to be the main regulatory step in the pathway and also in

cholesterol synthesis. Statins, drugs very commonly used

in the treatment of hypercholesterolemia, are competitive

inhibitors of HMG-CoA reductase. Mevalonate is phosphorylated

in two steps to mevalonate pyrophosphate,

which is then decarboxylated to isopentenyl pyrophosphate.

Isopentenyl pyrophosphate is not only an intermediate

but also the main building block for the synthesis of

dolichol and the side chain of coenzyme Q. It is isomerized

to dimethylallyl pyrophosphate, the substrate for farnesyl

synthase. This enzyme mediates a two-step reaction,

giving rise initially to the enzyme-bound, two-isoprenoid

intermediate geranyl pyrophosphate, followed by a new

condensation with isopentenyl pyrophosphate to the

three-isoprenoid farnesyl pyrophosphate.

All branch-point enzymes utilize farnesyl pyrophosphate

as substrate and they initiate the terminal part of

the synthesis. These enzymes are considered for overall

rate limiting and are consequently of utmost importance

in the regulation of the biosynthesis of the lipid in

question. In cholesterol synthesis, squalene synthase mediates

the head-to-head condensation of two molecules

of farnesyl pyrophosphate. cis-Prenyltransferase catalyzes

the 1-4 condensation of cis-isopentenyl pyrophosphate to

all-trans farnesyl pyrophosphate, which, after additional

modifications, generates dolichols with chain length between

16 and 23 isoprene units. trans-Prenyltransferase

mediates a series of addition reactions of isopentenyl

Dallner and Stocker

Figure 1 Coenzyme Q10, shown in its reduced ubiquinol-10

(top) and oxidized ubiquinone-10 (bottom) forms, consists of

a long hydrophobic side chain and a substituted benzoquinone

ring.

pyrophosphate to farnesyl pyrophosphate, resulting in alltrans

polyprenyl pyrophosphate, giving the side chain of

coenzyme Q. The chain length varies between different

species, and in humans, the chain is mostly decaprenyl

pyrophosphate, with some solanesyl pyrophosphate.

The next step in the biosynthesis requires the precursor

of the benzoquinone moiety, 4-hydroxybenzoate,

which itself is produced from tyrosine and is present in

excess amounts. After prenylation of 4-hydroxybenzoate,

the ring is modified by C-hydroxylations, decarboxylation,

O-methylations, and C-methylation. The final product

of the biosynthetic process is reduced coenzyme Q,

ready to serve as electron donor. The sequence of these reactions

has been studied so far mainly in bacteria and

yeast. In mammalian tissues, several genes have been

identified through complementary recognition with yeast

and the function for some of them was also established.

Isolated enzymes are not available at present, although

these will be required for the establishment of the details

of coenzyme Q synthesis in animal tissues.

  • Acetyl-CoA

  • Acetoacetyl-CoA

  • HMG-CoA

  • Mevalonate

  • Mevalonate-P

  • Mevalonate-PP

  • Isopentenyl-PP

  • Dimethylallyl-PP

  • Geranyl-PP

  • Tyrosine

  • Famesyl-PP

  • Protein isoprenylation

  • Geranylgeranyl-PP

  • Decaprenyl-4-OH-benzoate Squalene Polyprenyl-PP

  • Coenzyme Q Cholesterol Dolichol Dolichyl-P

  • 4-OH-Benzoate Decaprenyl-PP

  • Decaprenyl-4-OHbenzoate

  • transferase

  • trans-Prenyltransferase

  • Squalene

  • synthetase

  • cis-Prenyltransferase

  • HMG-CoA reductase

The mevalonate pathway leading to the biosynthesis of coenzyme

Q, cholesterol, dolichol, and dolichyl phosphate.

Enzymatic Reduction of CoQ

A major function of coenzyme Q is to serve as a lipid soluble

antioxidant. This requires CoQ to be present in its

reduced form, CoQH2, raising the question of how CoQ is

maintained in its reduced form,CoQH2. Ascorbate readily

reduces benzoquinone in a catalytic process controlled by

molecular oxygen, although this reduction is not likely of

biological importance, as the benzoquinone moiety of the

lipid-soluble CoQ10, when localized in biological membranes,

is not accessible to the water-soluble vitamin C.

Similarly, cytosolic DT-diaphorase, an enzyme proposed

earlier forCoQ10 reduction, is not efficient in reducing benzoquinones

containing long isoprene side chains. Based

on studies with the inhibitors rotenone and dicoumarol,

it is suggested that a cytosolic reduced nicotinamide adenine

dinucleotide phosphate (NADPH)-dependent CoQ

reductase, different from the mitochondrial reductase and

DT-diaphorase, is involved. More recently, the flavin adenine

dinucleotide (FAD)-containing enzymes, lipoamide

dehydrogenase and thioredoxin reductase, were found to

reduce CoQ in vitro with high efficiency. These enzymes

are homodimers, have a molecular weight of around

55 kDa, and belong to the family of pyridine nucleotide

disulfide oxidoreductases.

Coenzyme Q10 Enzymatic Functions

The most thoroughly studied function of coenzyme Q is

its participation in the mitochondrial electron transport

chain. The lipid is essential in respiration as it shuttles

electrons from nicotinamide nucleotide-linked (NADH)

dehydrogenase and succinate dehydrogenase (complexes

I and II) to the cytochrome system (complex III). During

respiration, coenzyme Q is present in fully oxidized, fully

reduced, and semiquinone forms. In the protonmotive Q

cycle, there is a cyclic electron transfer pathway through

complex III involving semiquinone that accounts for the

energy conservation at coupling site 2 of the respiratory

chain.

An electron transport system is also present in

the plasma membranes of cells for transferring electrons

across the membrane (3). The system is composed of a

quinone reductase located on the cytosolic side and is

thought to reduce CoQ in the presence of NADH. The

resulting CoQH2 then shuttles electrons to an NADH oxidase,

located on the external surface of the plasma membrane,

that reduces extracellular electron acceptors such

as the ascorbyl radical, in this case to ascorbate. This oxidase

is not related to the NADPH oxidase of phagocytes,

which functions independent of coenzyme Q. The precise

Coenzyme Q10

function(s) of the NADH oxidase remain(s) to be elucidated,

although it has been suggested to be involved in

the control of cell growth and differentiation, the maintenance

of extracellular ascorbic acid, the regulation of

cytosolic NAD+/NADH ratio, the induction of tyrosine

kinase, and early gene expression.

An electron transport system has also been proposed

to be present in lysosomal membranes, transferring

electrons from NADH to FAD, cytochrome b5, CoQ, and

molecular oxygen. This system could be involved in the

translocation of protons into the lysosomal lumen.

Coenzyme Q10 Non Enzymatic Functions

Modulation of Mitochondrial Pore Opening

Ions and solutes may penetrate the inner mitochondrial

membrane through specific transporters and ion channels.

It has been observed in vitro, during the accumulation of

Ca2+, that a permeability transition occurs and macromolecules

up to the size of 1500 Da cross the membrane

as a result of opening of an inner mitochondrial complex,

the membrane transition pore. A large number of different

compounds can open or close the membrane transition

pore. An opening in the inner mitochondrial membrane

is highly deleterious as it leads to loss of pyridine

nucleotides, hydrolysis of adenosine triphosphate (ATP),

disruption of ionic status, and elimination of the proton motive

force. Opening of the membrane transition pore

is suggested to be an early event in apoptosis, causing

activation of the caspase cascade through release of cytochrome

c. On the other hand, the membrane transition

pore may also have a physiological function by acting as

a fast Ca2+ release channel in mitochondria.

Various coenzyme Q analogs that contain the benzoquinone

moiety with or without a short saturated or unsaturated

side chain are modulators of the membrane transition

pore (4). They can inhibit, induce, or counteract the

effects of inhibitors and inducers. Endogenous CoQ10 may

play an important role in preventing the membrane transition

pore fromopening, as it counteracts several apoptotic

events, such asDNAfragmentation, cytochrome c release,

and membrane potential depolarization.

Uncoupling Protein Function

It is well established that the inner mitochondrial membrane

possesses uncoupling proteins that translocate protons

from the outside to the inside of the mitochondria. As

a result, the proton gradient established by the respiratory

chain is uncoupled from oxidative phosphorylation and

heat is produced instead of energy. In human tissues, five

uncoupling proteins have been identified, but only uncoupling

protein 1 has been studied in detail. It is present in

brown adipose tissue and participates in thermogenesis.

The content of uncoupling proteins in other tissues is low,

since uncoupling is not a common event. Uncoupling protein

2 is found in most tissues, and uncoupling protein 3

is abundant in skeletal muscle.

By overexpressing uncoupling proteins 1, 2, and 3

from Escherichia coli in liposomes, it was demonstrated

that coenzyme Q is an obligatory cofactor for the functioning

of uncoupling proteins, with the highest activity

obtained with CoQ10 (5). Uncoupling proteins were able

to transport protons only when CoQ10 was added to the

membranes in the presence of fatty acids. Low concentration

of ATP inhibited the activity. In this way, a proton is

delivered from a fatty acid to the uncoupling protein with

the assistance of CoQ10 in the inner mitochondrial membrane.

This is followed by the translocation of a proton to

the mitochondrial matrix by the uncoupling protein.

Coenzyme Q10 Antioxidant Activity

Approximately 1% to 2% of the molecular oxygen consumed

by mitochondria is converted to superoxide anion

radical and hydrogen peroxide. In addition, reactive oxygen

species are produced by other processes, including

autoxidation reactions, and by the action of enzymes such

as NADPH oxidases of phagocytes and other cells, mitochondrial

monoamine oxidase, flavin oxidases in peroxisomes,

and cytochromes P-450. Furthermore, nitric oxide,

generated by nitric oxide synthases, can interact with superoxide

and give rise to a number of reactive nitrogen

species. These reactive species have the potential to damage

lipids, proteins, and DNA,a process generally referred

to as “oxidative damage.” Antioxidants are enzymes, proteins,

or non proteinaceous agents that prevent the formation

of reactive oxygen and nitrogen species, or remove

these species or biomolecules that have been oxidatively

damaged.

Coenzyme Q is the only lipid-soluble antioxidant

synthesized endogenously (6). Its reduced form, CoQH2,

inhibits protein and DNA oxidation, but it is its effect

on lipid peroxidation that has been studied in detail.

Ubiquinol inhibits the peroxidation of cell membrane

lipids and also that of lipoprotein lipids present in the

circulation and in the walls of blood vessels. It has been

suggested that CoQH2 is a more efficient antioxidant than

vitamin E, for two reasons. First, its tissue (but not blood)

concentration exceeds several fold that of vitamin E. Second,

and similar to vitamin C, CoQH2 effectively reduces

-tocopheroxyl radical to -tocopherol, and by doing so

eliminates the potential pro-oxidant activities of vitamin

E. In fact, CoQH2 has been suggested to act as the first

line of nonenzymatic antioxidant defense against lipid derived

radicals. In addition, CoQH2 can inhibit the initiation

of lipid peroxidation by scavenging aqueous radical

oxidants.

As a result of its antioxidant action as a one-electron

reductant, CoQH2 is oxidized initially to its semiquinone

radical (CoQH•), which itself may be oxidized further to

CoQ, with the potential to generate the superoxide anion

radical. Regeneration of CoQH2 is therefore required for

coenzymeQto maintain its antioxidant activity. The effectiveness

of cellular reducing systems is suggested by the

fact that in most human tissues, the bulk of coenzyme Q

is recovered as CoQH2.

Coenzyme Q10 Effects on Atherosclerosis

Coenzyme Q10 can theoretically attenuate atherosclerosis

by protecting low-density lipoprotein from oxidation.

Ubiquinol-10 is present in human low-density lipoprotein

and, at physiological concentrations, prevents its oxidation

in vitro more efficiently than vitamin E. The antiatherogenic

effects are demonstrated in apolipoprotein

E-deficient mice fed a high-fat diet (7). Supplementation

with pharmacological doses of CoQ10 not only increased

aorticCoQ10 levels but also decreased the absolute

160 Dallner and Stocker

concentration of lipoprotein-associated lipid hydroperoxides

in atherosclerotic lesions. Most significantly, there

was a clear decrease in the size of atherosclerotic lesions in

the whole aorta. Whether these protective effects are solely

due to the antioxidant actions of coenzyme Q remains to

be established, as the tissue content of other markers of

oxidative stress, such as hydroxylated cholesteryl esters

and -tocopherylquinone, did not decrease.

Oral administration of CoQ10 to healthy humans results

in increased concentrations ofCoQ10H2 in circulating

lipoproteins (8), with reduction most likely taking place

in the intestine. Administration of CoQ10 also results in

uptake of the lipid into monocytes and lymphocytes but

not into granulocytes, whereas this dietary treatment increases

the vitamin E content in both mononuclear and

polymorphonuclear cells (9). The phospholipid composition

is modified selectively in mononuclear cells, which

display elevated amounts of arachidonic acid. Basal and

stimulated levels of 2-integrin CD11b and complement

receptor CD35, distributed on the surface of monocytes,

are also decreased by CoQ10 supplementation. This may

contribute to the antiatherogenic effect of dietary CoQ10,

since CD11b contributes to the recruitment of monocytes

to the vessel wall during atherogenesis.

Coenzyme Q10 Effects on Blood Flow and Pressure

It is uncertain whether or not CoQ10 reduces blood pressure

in the long-term management of primary hypertension

(10). It is possible that any blood pressure lowering

effect is indirect—perhaps via improved diastolic and endothelial

function. Endothelial dysfunction of the arteries

has potentially serious consequences and is commonly

seen in patients with established cardiovascular disease

or elevated risk factors. Ubiquinone supplementation improves

endothelial function measured as flow-mediated

dilatation of the brachial artery in patients with uncomplicated

type 2 diabetes and dyslipidemia but not in hypercholesterolemic

subjects (11). In diabetic patients, CoQ10

administration has also been found to decrease systolic

blood pressure and HbA1C, but not F2-isoprostanes, suggesting

that the protective effects may have been unrelated

in the decrease of vascular oxidative stress.

Potential Anti-inflammatory Effects

There is some evidence that pharmacological doses of

CoQ10 may have anti-inflammatory effects in vivo under

some conditions (12). This is an area worthy of further

investigations, as inflammation is part of the etiology in

many diseases, such as cardiovascular diseases, diabetes,

and Alzheimer disease. An anti-inflammatory effect could

help explain why positive health effects are reported in a

number of investigations when uptake of the lipid into a

specific organ was limited.

Coenzyme Q10 PHYSIOLOGY

Tissue Distribution

CoQ10 is present in all human tissues in highly variable

amounts (Table 1). The amounts are dependent on several

factors, the most important under normal physiological

conditions is the age (see sect. “Aging”). The highest

amount is found in the heart (114 g/g wet weight) (13).

Concentration of Coenzyme Q10 in Different Adult Human Tissues

Tissue CoQ10 (g/g tissue)

  • Brain 13

  • Thyroid 25

  • Lung 8

  • Heart 114

  • Stomach 12

  • Small intestine 12

  • Colon 11

  • Liver 55

  • Pancreas 33

  • Spleen 25

  • Kidney 67

  • Testis 11

  • Muscle 40

In the kidney, liver, muscle, pancreas, spleen, and thyroid,

the CoQ10 content is between 25 and 67 g/g, and

in the brain, lung, testis, intestine, colon, and ventricle,

it is between 8 and 13 g/g. This variation is explained

by histological structure, and consequently there are great

variations within the same organ. For example, in different

regions of the bovine brain, the amount of CoQ10

varies between 25 g/g (striatum) and 3 g/g (white matter).

Rapid extraction and direct measurement by HPLC

show that the major part of coenzyme Q10 in tissues, with

the exception of brain and lung, is the reduced form,

CoQ10H2.

Intracellular Distribution

In rat liver, the highest amount of coenzymeQ9 is found in

the outer and inner mitochondrial membranes, lysosomes,

and Golgi vesicles (1.9–2.6 g/mg protein); the concentration

in plasma membranes is 0.7 g/g, and it is 0.2 to

0.3 g/g in the nuclear envelope, rough and smooth microsomes,

and peroxisomes (Table 2) (13). The distribution

pattern is quite different from that of other neutral lipids.

For example, the major part of dolichol is localized in lysosomes,

that of cholesterol in plasma membranes, and that

of vitamin E in Golgi vesicles.

Within membranes, coenzyme Q10 has a specific arrangement,

with the decaprenoid side chain located in

the central hydrophobic region, between the bilayer of

phospholipid fatty acids. The functionally active group,

the benzoquinone ring, is located on the outer or inner

 Concentration of Coenzyme Q9 in Different Subcellular

Organelles of Rat Liver

Organelle CoQ9 (g/mg protein)

  • Nuclear envelope 0.2

  • Mitochondria 1.4

  • Outer membrane 2.2

  • Inner membrane 1.9

  • Microsomes 0.2

  • Rough microsomes 0.2

  • Smooth microsomes 0.3

  • Lysosomes 1.9

  • Lysosomal membrane 0.4

  • Golgi vesicles 2.6

  • Peroxisomes 0.3

  • Plasma membrane 0.7

  • Coenzyme Q10 161

surface of the membrane depending on the functional requirement.

Because of this central localization, coenzyme

Q10 destabilizes membranes, decreases the order of phospholipid

fatty acids, and increases permeability. These effects

are in contrast to those of cholesterol, which is located

adjacent to fatty acids on one side of the bilayer and that

stabilizes the membrane, increases the order of its lipids,

and decreases membrane permeability.

Transport

While the mevalonate pathway from acetyl-CoA to farnesyl

pyrophosphate is mainly cytoplasmic, the terminal

parts of coenzyme Q biosynthesis are localized in the mitochondria

and endoplasmic reticulum (ER)-Golgi system.

The mitochondrial inner membrane probably receives its

lipid from the biosynthetic system associated with the

matrix–inner membrane space. Newly synthesized verylow-

density lipoproteins assembled in the ER-Golgi system

also contain de novo synthesized coenzyme Q, which

has to be synthesized at this location, like the other lipid

and protein components of the lipoproteins. It is most

probable that the various other cellular membranes also

receive their constitutive coenzyme Q from the ER-Golgi

system, as is the case with other lipids. Judging by studies

in plants in vivo and with reconstituted cell-free systems,

intracellular transport of coenzyme Q is a vesiclemediated,

ATP-dependent process, and cytosolic carrier

proteins may also be involved.

Due to its hydrophobicity, the existence of a binding/

transfer protein for coenzyme Q seems plausible,

and recently saposin B has been suggested to serve this

function (14). Aqueous saposin B was reported to extract

and bind coenzyme Q dissolved in hexane to form

a saposin B-coenzyme Q complex, with the lipid-binding

affinity decreasing in the order: CoQ10>CoQ9>CoQ7

-

tocopherol

cholesterol (no binding).

Under normal conditions, all organs and tissues synthesize

sufficient coenzyme Q, so that external supply is

not required. Coenzyme Q present in small amounts in all

circulating lipoproteins is derived from very-low-density

lipoprotein newly synthesized and discharged by the liver.

It likely functions as an antioxidant and protects lipoproteins,

with restricted redistribution among them. In the

case of dietary coenzyme Q, lipoproteins are the carriers

in the circulation and interact with at least some types of

tissues for cargo delivery. Thus, the situation differs from

that of cholesterol, in which case several organs depend

on external supply from the diet or the liver.

Coenzyme Q10 Bioavailability Plasma

The uptake of coenzyme Q from the intestine occurs at

a low rate, with only 2% to 4% of the dietary lipid appearing

in the circulation. The uptake mechanism has not

been studied so far but is probably similar to that of vitamin

E and mediated by chylomicrons. In rats, dietary

CoQ10 appears as CoQ10H2 in mesenteric triacylglycerol rich

lipoproteins, which enter the circulation and are converted

by lipoprotein lipase to chylomicron remnants,

which are then cleared rapidly by the liver. Some of this

diet-derived coenzyme reappears in the circulation, perhaps

as a result of hepatic synthesis and release of verylow-

density lipoprotein. Depending on the diet, in healthy

human controls the amounts of coenzyme Q in very-lowdensity,

low-density, and high-density lipoproteins are 1.2,

1.0, and 0.1 nmol/mg protein, respectively. After dietary

supplementation (3 °ø 100 mg CoQ10/day for 11 days),

the amounts are 3.2, 3.5, and 0.3 nmol/mg protein, respectively.

These data are consistent with the notion that

circulating coenzyme Q redistributes among lipoproteins

to protect them against oxidation.

For most tissues, the low bioavailability of CoQ limits

the ability of supplements to restore normal tissue levels

of CoQH2 where deficiency exist. There are several

potential ways to approach this problem, including administration

of the lipid in reduced form, and increasing

bioavailability by either derivatization or administering

CoQ in association with cyclodextrins. “Mitoquinone,” a

cationic modified form of CoQ attained by coupling to

triphenylphosphonium and targeted to mitochondria to

improve mitochondrial function, has received much interest

recently (15). However, it is important to point out that

mitoquinone is not a form of CoQ naturally occurring in

human tissue, and the increase in superoxide production

observed after uptake of mitoquinone into mitochondria is

of potential concern (16). A potential alternative approach

to increase CoQ in blood and tissues may be via drugs that

stimulate the endogenous synthesis. This would not only

elevate the amount of the lipid but possibly also direct

it to the appropriate location. Polyisoprenoid epoxides

in tissue culture and peroxisome proliferator-activated

receptor- agonists in rodents increase CoQ synthesis and

amounts; however, no drug for this purpose is presently

available for humans.

Blood Cells

Red blood cells contain very small amounts of coenzyme

Q. In lymphocytes, the content of CoQ10 is doubled after

one week of dietary supplementation with this lipid, and

this enhances both the activity of DNA repair enzymes

and the resistance of DNA to hydrogen peroxide-induced

oxidation (17). Two months of CoQ10 supply to humans

increases the ratio of T4/T8 lymphocytes (18), and an increase

in the number of lymphocytes has been noted after

three months of dietary supply of this lipid. Ten weeks

of CoQ10 administration to healthy subjects elevated the

lipid content by 50% in monocytes, but no increase was

observed in polymorphonuclear cells.

Tissues

There remains some controversy regarding the bioavailability

of dietary coenzyme Q in different tissues. In rats,

the liver, spleen, adrenals, ovaries, and arteries take up a

sizeable amount of dietary coenzyme Q (19). Under normal

physiological conditions, very limited uptake may

also occur in the heart, pancreas, pituitary gland, testis,

and thymus. No uptake is apparent in the kidney, muscle,

brain, and thyroid gland. However, uptake into rat brain

has been reported—possibly the outcome of the specific

conditions employed. Similarly, in mice, some, but not all,

investigators have reported uptake into tissues. Derivatization

of coenzyme Q by succinylation and acetylation

increases its uptake into blood but not into various organs.

What is clear is that under normal conditions, the

bioavailability of dietary coenzyme Q in most tissues is

162 Dallner and Stocker

limited. This may be explained by its distribution and

functional requirement. Under normal conditions, all cells

synthesize sufficient lipid, so that external supply is not

required. Exogenous coenzyme Q taken up by the liver

does not appear in mitochondria, which house the bulk of

this cellular lipid, but is found mainly in nonmembranous

compartments, such as the lysosomal lumen.

The situation is, however, different in states of severe

coenzyme Q deficiency. Genetic modifications causing

low levels of coenzyme Q have serious consequences

for neuronal and muscular function (20). In children

with genetic coenzyme Q deficiency, dietary supplementation

greatly alleviates pathological conditions and reestablishes

mitochondrial and other functions. Limited

studies with biopsy samples from patients with cardiomyopathy

also indicate that the cardiac levels of coenzyme

Q are decreased and may be increased by dietary supplementation

with the lipid. Thus, it appears that uptake and

appropriate cellular distribution of coenzyme Q occur if

there is a requirement for the lipid.

Direct organ uptake of sizeable amounts is not necessarily

the only way of action of coenzyme Q, as other

redox-active substances can act by signaling, serving as

primary ligands or secondary transducers. Thus, the presence

of coenzymeQin the blood may impact on the vascular

system, the production of cytokines, the expression of

adhesion molecules, and the production of prostaglandins

and leukotrienes. The possibility that metabolites of coenzyme

Q influence metabolic processes has not yet been

investigated.

Catabolism

The short half-life of coenzyme Q, ranging between 49

and 125 hours in various tissues  indicates that

the lipid is subject to rapid catabolism in all tissues.

The main urinary metabolites identified have an unchanged

and fully substituted aromatic ring with a short side chain

containing five to seven carbon atoms and a carboxyl

group at the -end (21). Phosphorylated forms of these

metabolites are also recovered from nonhepatic tissues.

These water-soluble metabolites are transferred to the circulation

and are excreted by the kidney through urine. In

the liver, the coenzyme Q metabolites become conjugated

to glucuronic acid for fecal removal via bile.

Table 3 Half-life of CoQ9 in Rat Tissues

Tissue Half-life (hr)

  • Brain 90

  • Thyroid 49

  • Thymus 104

  • Heart 59

  • Stomach 72

  • Small intestine 54

  • Colon 54

  • Liver 79

  • Pancreas 94

  • Spleen 64

  • Kidney 125

  • Testis 50

  • Muscle 50

Regulation of Tissue Coenzyme Q Content

In contrast to cholesterol, coenzyme Q does not appear

to be subject to dietary or diurnal variations. However, a

number of treatments decrease the content of the lipid

in experimental systems. Administration of thiouracil,

which inhibits thyroid gland function, decreases liver

coenzyme Q. Oral administration of vitamin A also lowers

hepatic coenzyme Q. In selenium-deficient rats, the coenzyme

Q content of the liver is decreased by 50%, and the

amount of the lipid is also lowered in the heart and kidney

(but not muscle). A protein-free diet for three weeks lowers

coenzyme Q content in the liver and heart but not in

the kidney, spleen, and brain. As indicated earlier, HMGCoA

reductase controls cholesterol synthesis because the

branch-point enzyme squalene synthase has a low affinity

for farnesyl pyrophosphate, so that its pool size is the

main regulatory factor (22). By contrast, the branch-point

enzyme of coenzyme synthesis, trans-prenyltransferase,

has a comparatively higher affinity for farnesyl pyrophosphate,

so that a decrease in this substrate does not generally

lower the rate of coenzyme Q synthesis. It appears,

however, that the doses of statins employed for the

treatment of hypercholesterolemia result in inhibition of

synthesis, as the coenzyme Q concentration decreases in

several tissues (23).

As mentioned earlier, the bioavailability of dietary

coenzyme Q is limited. For this reason, it would be advantageous

to find compounds that elevate tissue concentrations

of coenzyme Q by increasing its biosynthesis. In

rats and mice, treatment with peroxisomal inducers, such

as clofibrate, phthalates, and acetylsalicylic acid, induces

coenzyme synthesis in most organs and elevates its concentration

in all subcellular organelles (24). The upregulation

takes place by interaction with a nuclear receptor:

peroxisomal proliferator receptor-. This receptor interacts

with a number of genes, resulting in the increased

synthesis of several enzymes, many of them connected

to lipid metabolism. However, peroxisomal proliferator

receptor- is poorly expressed in human tissue, and it

is not known to what extent this transcription factor is

involved in coenzyme Q metabolism. Agonists or antagonists

to various nuclear receptors may be a future approach

to the upregulation of coenzyme Q biosynthesis

and its concentration in human tissues.

Hormones control coenzyme Q metabolism, but

their method of action is not known in detail. Growth hormone,

thyroxin, dehydroepiandrosterone, and cortisone

elevate coenzyme Q levels in rat liver to various extents.

A liver-specific increase of coenzyme Q occurs in rat and

mice after two to three weeks stay in the cold room (+4◦C).

Vitamin A deficiency more than doubles the coenzyme Q

level in liver mitochondria and more than trebles that in

liver microsomes. Squalestatin 1, an inhibitor of squalene

synthase, greatly increases coenzyme Q synthesis by increasing

the farnesyl pyrophosphate pool and saturating

trans-prenyltransferase.

COENZYME Q10 DEFICIENCY

Genetic Disorders

Coenzyme Q deficiency is an autosomal recessive disorder

that may present itself in the form of myopathy,

Coenzyme Q10

encephalopathy and renal disease, or ataxia (20). The

myopathic form is characterized by substantial loss of

muscle coenzyme Q, muscle weakness, myoglobinuria,

ragged-red fibers, and lactic acidosis. Patients with encephalopathy

and renal involvement possess a more general

disease, with myopia, deafness, renal failure, ataxia,

amyotrophy, and locomotor disability. In these cases,

coenzyme Q is undetectable or present at very low levels

in cultured fibroblasts. In the ataxic form of deficiency,

weakness, cerebellar ataxia, cerebellar atrophy,

seizures, and mental retardation dominate, and low levels

of coenzyme Q are found in the skeletal muscle.

Various types of mutations have been found to be responsible

for decreased synthesis of CoQ (25). Most of

the mutations are of the primary type, affecting proteins

related to the biosynthesis of the lipid. COOQ1-PDSS1

and -PDSS2 (two subunits of decaprenyl diphosphate

synthase), COOQ2 (decaprenyl-4-hydroxybenzoate transferase),

COOQ8 (CABC1 or ADCK3, a putative protein

kinase), and COOQ9 (nonidentified function) are genes

established in this group. There are also secondary forms

of deficiency caused by mutations in genes not involved

in coenzyme Q biosynthesis. Mutations in APTX (encoding

aprataxin) and ETFDH (multiple acyl-CoA dehydrogenase

deficiency caused by defects in electron transfer

flavoprotein or ETF-ubiquinone oxidoreductase) also result

in CoQ deficiency.

The cases described in the literature probably represent

extreme forms of coenzyme Q deficiency, seriously

affecting mitochondrial functions. Moderate coenzyme Q

deficiency is probably more common, though this requires

verification by appropriate analysis of tissue biopsy samples.

Unfortunately, the coenzyme Q content in blood often

does not mirror the tissue concentration of the lipid,

and it is highly desirable to develop methods to estimate

moderate degrees of coenzyme Q deficiency. At present,

diagnosis depends on measuring the coenzyme Q content

in muscle biopsy samples, cultured fibroblasts, and

lymphoblasts, or analyzing mitochondrial respiration and

enzymes that require coenzyme Q as intermediate.

CoQ deficiency is of special interest since it is the

only treatable mitochondrial disease and oral administration

of CoQ re-establishes normal functions. Early diagnosis

before development of clinical symptoms is of outmost

importance since established kidney and brain damages

maynot be completely reversible. The treatment, however,

stops the process and the improvement is dramatic as children

leave the wheel-chair state and are able to perform

various activities. The problem is that at present diagnosis

requires a muscle biopsy and analysis of mitochondrial

functions. This does not allow screening of larger populations.

Therefore, development of simplified diagnostic

procedures would be of great interest also for diagnosis

of less severe cases, probably present in relatively high

numbers.

Aging

In human organs, the coenzyme content increases threeto

fivefold during the first 20 years after birth, followed

by a continuous decrease, so that in some tissues the concentration

may be lower at 80 years than at birth (Table 4)

(26). The decrease is less pronounced in the brain, where

Coenzyme Q10 Content (g/g) with Age in Human Organs and Human Brain Age:

  • Human organs 2 days 2 yr 20 yr 41 yr 80 yr

  • Lung 2.2 6.4 6.0 6.5 3.1

  • Heart 36.7 78.5 110.0 75.0 47.2

  • Spleen 20.7 30.2 32.8 28.6 13.1

  • Liver 13.9 45.1 61.2 58.3 50.8

  • Kidney 17.4 53.4 98.0 71.1 64.0

  • Pancreas 9.2 38.2 21.0 19.3 6.5

  • Adrenal 17.5 57.9 16.1 12.2 8.5

  • Human brain 34 yr 55 yr 70 yr 90 yr

  • Nucleus caudatus 11.6 11.7 10.5 6.6

  • Gray matter 16.4 16.2 16.0 13.5

  • Hippocampus 14.5 13.8 12.6 8.0

  • Pons 11.6 11.7 10.5 6.6

  • Medulla oblongata 11.1 10.8 10.0 4.7

  • White matter 5.0 5.0 4.9 2.0

  • Cerebellum 13.2 13.0 12.9 11.0

it mainly takes place between 70 and 90 years, and its extent,

between 20% and 60%, depends on the localization.

This pattern is different from that seen for other lipids.

In most tissues, the content of cholesterol and phospholipids

remains unchanged during the whole life period,

whereas the amounts of dolichyl phosphate and especially

dolichol increase greatly with age. It is unclear whether

the decrease in coenzyme Q content is caused by its lowering

in all or some selected cellular membranes or, alternatively,

by other changes such as decreased number of

mitochondria.

Cardiomyopathy

The uptake of dietary coenzyme Q into heart muscle is

low in both rats and humans, but it may increase significantly

in various forms of cardiomyopathy (27).A Number

of clinical trials performed during the last 30 years suggest

that heart functional performance may be improved

modestly by dietary coenzyme supplementation (28,29).

In congestive heart failure, improvements have been reported

for ejection fraction, stroke volume, and cardiac

output. Patients with angina may respond with improved

myocardial efficiency. Reperfusion injury, such as after

heart valve replacement and coronary artery bypass graft

surgery, includes oxidative damage, and treatment of patients

with coenzyme Q prior to surgery may lead to decreased

oxidative damage and functional improvement.

However, the benefits reported have not been consistent,

and despite the existence of a large body of literature, there

remains a need for large, long-term, and well-designed

trials to establish unambiguously whether CoQ10 supplements

are beneficial in the setting of cardiomyopathy and

the failing heart.

Neurological Disorders

Judging by extensive animal studies, a number of neurological

diseases involve mitochondrial dysfunction and

oxidative stress. The positive effects obtained with coenzyme

Q treatment in these models suggest that supplementation

may also be beneficial in humans (30). Patients

with early Parkinson disease were subjected to a trial

164 Dallner and Stocker

in which the placebo group was compared with groups

supplemented for 16 months with coenzyme Q up to

daily doses of 1200 mg. It was found that coenzyme Q

slowed the progressive functional deterioration, with the

best results obtained with the highest dose. Platelets from

these patients had decreased coenzymeQcontent and also

showed reduced activity of mitochondrial complex I and

complex II/III. The ratio of CoQ10H2 to CoQ10 was also

decreased in these platelets, indicative of the presence of

oxidative stress. Upon supplementation, the CoQ10 content

in the platelets increased and complex I activity was

also elevated. In Huntington disease, magnetic resonance

spectroscopy detected increased lactate concentration in

the cerebral cortex. Administration of CoQ10 caused a significant

decrease in lactate that reversed upon discontinuation

of the therapy.

Deficiency of frataxin, a regulator of mitochondrial

iron content, causes Friedreich ataxia. When patients with

this disease were treated with coenzyme Q and vitamin

E for six months, progression of their neurological

deficits was slowed down, associated with an improvement

in cardiac and skeletal muscle energy metabolism

(31). Treatment of these patients with idebenone, an analog

of coenzyme Q, reduced heart hypertrophy and improved

heart muscle function. In several studies, patients

with mitochondrial encephalopathy, lactic acidosis, and

strokes (MELAS) displayed significant improvement after

coenzymeQor idebenone treatment (32). Several other

trials were also performed during recent years with variable

results. Since there are subtypes of individual neurodegenerative

diseases, large numbers of patients are required

to obtain reliable results, which is often difficult to

accomplish.

Statin Therapy

Statins are the drugs most commonly used for the treatment

of hypercholesterolemia, and, in addition to efficient

cholesterol lowering, they also have anti-inflammatory activities.

The basis for their use is that inhibition of HMGCoA

reductase decreases the farnesyl pyrophosphate pool

to such an extent that squalene synthase, which catalyzes

the terminal regulatory step in cholesterol synthesis, is no

longer saturated, thereby inhibiting overall synthesis (22).

It appears, however, that the extent to which the farnesyl

pyrophosphate pool is decreased by therapeutic doses

of the drug also affects the saturation of trans- and cisprenyltransferases

in spite of the fact that these latter enzymes

have a higher affinity for farnesyl pyrophosphate.

Consequently, synthesis of both coenzyme Q and dolichol

is inhibited. Rats treated with statins exhibit decreased

levels of coenzyme Q, dolichol, and dolichyl phosphate

in heart and muscle, and the same is probably also true

in humans. In humans, statin treatment significantly decreases

blood coenzyme Q concentration (33), although

the clinical significance of this phenomenon remains to be

established. Various degrees of myopathy, myalgia, and

rhabdomyolysis have been reported in statin-treated patients,

and it is possible, but not proven, that these conditions

are related to decreased muscle coenzyme content.

Initial trials of CoQ10 supplementation in patients with

statin-induced myopathy have provided variable results

(34). Given the widespread use of statins, it is important

that additional studies address a possible causal link between

these side effects of statin treatment and altered

tissue coenzyme Q content.

Exercise

During endurance exercise training, the coenzyme Q concentration

increases in rat muscle on a weight basis due

to an increase in mitochondrial mass.

After four days of high-intensity training, the coenzyme Q content in the

exposed muscles of healthy persons is unchanged (35).

Supplementation (120 mg/day) doubles the coenzyme Q

concentration in the plasma, but there is no change in the

muscle content as judged by HPLC analysis of the tissue

homogenate and isolated mitochondrial fraction in both

control and trained subjects.

Dosage

So far, no toxic or unwanted side effects have been described

for CoQ10 supplements in humans, not even after

ingestion in gram quantities. In most studies, 100 to

200 mg has been given per day in two doses. In genetic

disorders, in the case of adults, the dose may increase to

300 mg/day and in neurological diseases, up to 400 mg/

day or more. In the latter case, in the frame of large multicenter

trials, doses up to 2400 mg have been supplied. A

patent on the use of statins combined with coenzyme Q

has expired recently, although this combined preparation

has not been manufactured so far. Now it may be possible

for the pharmaceutical industry to introduce capsules

containing statins and coenzyme Q in order to decrease

the potential for muscle damage. In this case, relatively

low doses of CoQ10 (e.g., 50 or 100 mg/day) appear to be

appropriate.

 

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