Human Coenzyme Q10 Research Articles

Extracellular coenzyme Q10 (CoQ10) is reduced to ubiquinol-10 by intact Hep G2 cells independent of intracellular CoQ10 reduction

Coenzyme Q10 (CoQ10) is an essential factor in the mitochondrial respiratory chain and is closely associated with ATP production in humans. It is known that orally administered CoQ10 in humans is rapidly reduced, and most is detected as a reduced form, ubiquinol-10 (CoQ10H2), in serum. However, the mechanism of exogenous CoQ10 reduction in vivo is unclear. Therefore, in order to clarify how CoQ10 is reduced to CoQ10H2, we conducted a study using human liver cancer cell line Hep G2 cells, which show strong intracellular CoQ10-reducing activity. When intact cells were incubated with CoQ10, the exogenously added CoQ10 was incorporated into the cells, time-, concentration-, and temperature-dependently, and 50–80% of that was detected as CoQ10H2. On the other hand, a part of the extracellular CoQ10 was also detected as CoQ10H2, and the amount was greater than that of the intracellular CoQ10H2. Furthermore, the CoQ10-loaded cells did not leak the intracellular CoQ10H2 (or CoQ10) to the outside of the cells, and modulation of the extracellular CoQ10H2 amount had little effect on the intracellular CoQ10 or CoQ10H2 contents, suggesting the existence of an individual mechanism of CoQ10 reduction inside and outside the cells. Moreover, intact cells could reduce CoQ10 in low-density lipoprotein to CoQ10H2. Therefore, we concluded that a novel CoQ10-reducing mechanism may exist in the plasma membrane, probably the outer surface, of Hep G2 cells, and it may work to reduce extracellular CoQ10 and/or maintain extracellular CoQ10H2.

Vitamin K2 cannot substitute Coenzyme Q10 as electron carrier in the mitochondrial respiratory chain of mammalian cells

Coenzyme Q10 (CoQ10) deficiencies are a group of heterogeneous conditions that respond to ubiquinone administration if treated soon after the onset of symptoms. However, this treatment is only partially effective due to its poor bioavailability. We tested whether vitamin K2, which was reported to act as a mitochondrial electron carrier in D. melanogaster, could mimic ubiquinone function in human CoQ10 deficient cell lines, and in yeast carrying mutations in genes required for coenzyme Q6 (CoQ6) biosynthesis. We found that vitamin K2, despite entering into mitochondria, restored neither electron flow in the respiratory chain, nor ATP synthesis. Conversely, coenzyme Q4 (CoQ4), an analog of CoQ10 with a shorter isoprenoid side chain, could efficiently substitute its function. Given its better solubility, CoQ4 could represent an alternative to CoQ10 in patients with both primary and secondary CoQ10 deficiencies.

Mitochondrial Dysregulation and Impaired Autophagy in iPSC-Derived Dopaminergic Neurons of Multiple System Atrophy.

SummaryMultiple system atrophy (MSA) is a progressive neurodegenerative disease that affects several areas of the CNS, whose pathogenesis is still widely unclear and for which an effective treatment is lacking. We have generated induced pluripotent stem cell-derived dopaminergic neurons from four MSA patients and four healthy controls and from two monozygotic twins discordant for the disease. In this model, we have demonstrated an aberrant autophagic flow and a mitochondrial dysregulation involving respiratory chain activity, mitochondrial content, and CoQ10 biosynthesis. These defective mechanisms may contribute to the onset of the disease, representing potential therapeutic targets.

Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization.

Bioavailability of supplements with coenzyme Q10 (CoQ10) in humans seems to depend on the excipients of formulations and on physiological characteristics of the individuals. The aim of this study was to determine which factors presented in CoQ10 supplements affect the different response to CoQ10 in humans. We tested seven different supplement formulations containing 100 mg of CoQ10 in 14 young, healthy individuals. Bioavailability was measured as area under the curve of plasma CoQ10 levels over 48 h after ingestion of a single dose. Measurements were repeated in the same group of 14 volunteers in a double-blind crossover design with a minimum of 4 wk washout between intakes. Bioavailability of the formulations showed large differences that were statistically significant. The two best absorbable formulations were soft-gel capsules containing ubiquinone (oxidized CoQ10) or ubiquinol (reduced CoQ10). The matrix used to dissolve CoQ10 and the proportion and addition of preservatives such as vitamin C affected the bioavailability of CoQ10. Although control measurements documented that all formulations contained 100 mg of either CoQ10 or ubiquinol, some of the participants showed high and others lower capacity to reach high increase of CoQ10 in blood, indicating the participation of individual unknown physiological factors. This study highlights the importance of individually adapted selection of best formulations to reach the highest bioavailability of CoQ10 in humans.

Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease

Controversies surround the usefulness of Coenzyme Q10 (CoQ10) in Huntington's disease (HD), an autosomal dominant, fatal, neurodegenerative disease with no cure or disease modifying treatment. CoQ10, an endogenous substrate for electron transport and an anti-oxidant, has been shown in some but not all studies to improve symptoms and survival in mouse models of HD. Previous studies have been conducted in fast-progressing models that better mimic the juvenile forms of HD than the much more common middle-age onset form, possibly accounting for mixed results. Establishing the usefulness of CoQ10 to alter HD disease course in a model that better recapitulates the progressive features of the human disorder is important because clinical trials of CoQ10, which is safe and well tolerated, are being planned in patients. The CAG140 knock-in (KI) mouse model of HD in which an expanded (approximately 120) CAG repeat is inserted in the mouse gene provides a model of the mutation in the proper genomic and protein context. These mice display progressive motor, cognitive and emotional anomalies, transcriptional disturbances and late striatal degeneration. Homozygote mutant CAG140 KI mice and wild-type littermates were fed CoQ10 (0.2%, 0.6%) in chow, and behavioral and pathological markers of disease were examined. CoQ10 improved early behavioral deficits and normalized some transcriptional deficits without altering huntingtin aggregates in striatum. The lower dose (0.2%) was more beneficial than 0.6%. Similar to previous studies, this low dose also induced deleterious effects in open field and rotarod in WT mice, however these effects are of unclear clinical significance in view of the excellent safety profile of CoQ10 in humans. These data confirm that CoQ10 may be beneficial in HD but suggest that maximum benefit may be observed when treatment is begun at early stages of the disease and that dosage may be critical.

Improved Thermal Property and Absorption of Coenzyme Q10 in Humans Using Cyclodextrin

Coenzyme Q10 (CoQ10) is a well-known antioxidant agent that has low solubility in water and poor absorption in humans. CoQ10-cyclodextrin (CD) complex powders containing 20-24% (w/w) CoQ10 were prepared to investigate the effects of different CDs on three properties of CoQ10: aqueous solubility, heat of fusion, and absorption in humans. The aqueous solubility of CoQ10 was increased by α-CD and dextrin, while β-CD, γ-CD and β-Iso® formed an insoluble complex with CoQ10. β-CD, γ-CD and β-Iso® improved the thermal property of CoQ10, as determined by differential scanning calorimetry. That is, β-CD, γ-CD and β-Iso® most likely formed complexes with CoQ10, as the CoQ10 endothermic peak obtained by differential scanning calorimetry greatly decreased in the presence of these compounds. For the absorption studies, 20 healthy female volunteers were divided randomly into four groups and orally administered either CoQ10, the CoQ10-β-CD complex, CoQ10-γ-CD complex or CoQ10-β-Iso® complex containing 0.30 g CoQ10 under fasting conditions. The concentration of CoQ10 in plasma before and 2, 4, 6, 8 and 24 h after sample administration was measured by HPLC analysis, and the plasma concentration of exogenous CoQ10 was calculated as the plasma concentration of CoQ10 before administration subtracted from the value after administration. The area under the plasma exogenous CoQ10 concentration/time-course curve from 0 to 8 h of the three complex groups was significantly higher than that of the CoQ10 group, indicating that β-CD, γ-CD and β-Iso® accelerate the absorption of CoQ10 in humans.

Abstract: S4-11 COENZYME Q10 LEVELS AND VASCULAR FUNCTION IN PATIENTS ON LONG-TERM STATIN THERAPY FOR FAMILIAL HYPERCHOLESTEROLEMIA

Bioavailability of supplements with coenzyme Q10 (CoQ10) in humans seems to depend on the excipients of formulations and on physiological characteristics of the individuals. The aim of this study was to determine which factors presented in CoQ10 supplements affect the different response to CoQ10 in humans.We tested seven different supplement formulations containing 100 mg of CoQ10 in 14 young, healthy individuals. Bioavailability was measured as area under the curve of plasma CoQ10 levels over 48 h after ingestion of a single dose. Measurements were repeated in the same group of 14 volunteers in a double-blind crossover design with a minimum of 4 wk washout between intakes.Bioavailability of the formulations showed large differences that were statistically significant. The two best absorbable formulations were soft-gel capsules containing ubiquinone (oxidized CoQ10) or ubiquinol (reduced CoQ10). The matrix used to dissolve CoQ10 and the proportion and addition of preservatives such as vitamin C affected the bioavailability of CoQ10. Although control measurements documented that all formulations contained 100 mg of either CoQ10 or ubiquinol, some of the participants showed high and others lower capacity to reach high increase of CoQ10 in blood, indicating the participation of individual unknown physiological factors.This study highlights the importance of individually adapted selection of best formulations to reach the highest bioavailability of CoQ10 in humans.

Cerebrospinal Fluid (CSF) Concentration of Coenzyme Q10 in Clinical Practice, A Breaking News Finding in Humans

There is significant interest in coenzyme Q10(CoQ10) as a potential treatment for neurodegenerative diseases and in its promise as a neuroprotectant. Experimental studies indicate that CoQ10 can protect against brain disorders by in- hibiting neuronal damage. There is a need to demonstrate CSF levels of CoQ10 in humans. Subjects and Methods: After clearance from the hospital ethical committee, all of the subjects presenting with a suspicion of neurological diseases were asked to give written informed consent for lumber puncture for testing of CSF. CoQ10 con- centration in CSF was examined by HPLC with electrochemical detection system at the Division of Molecular Neuroge- netics, College of Physicians and Surgeons, New York,USA. Clinical and laboratory data were obtained from all of the patients (n=38) to confirm clinical diagnosis. CAT scan of the head was done in all of the patients presenting with seizures and stroke. All CSF specimens were examined for cells, sugar and proteins and those suspected of being contaminated with blood were excluded from study. Results: The age varied between 17 to 60 years and the number of males (n=16) were less than females (n=21). Patients were suffering from epileptic seizures (n=19), tuberculous meningitis (n=5) and stroke (n=4). The rest of the 9 patients presented with headache of non-neurological condition with or without fever. The CSF concentration of CoQ10 was sig- nificantly lower among these subjects; mean ± SD ( 0.59 ± 0.12 ng/ml), which appears to represent the normal level of CoQ10 in healthy subjects. The concentration of CoQ10 in CSF tended to be higher among patients with TBM ( 1.27 ± 0.60 ng/ml), seizures ( 1.26 ± 0.34 ng/ml) and stroke ( 0.83 ± 0.20 ng/ml) compared to subjects without neurological problem. These findings indicate that there is greater release of CoQ10 or increased synthesis in the tissues possibly to fight against oxidative stress caused by brain disorders. Conclusions: This study shows that the level of CoQ10 in the csf is substantially lower than that in serum by three orders of magnitude and tends to be elevated under pathological conditions associated with brain injury. Further studies in a larger number of subjects are necessary to confirm our findings.

Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis

Coenzyme Q(10) (CoQ(10)) deficiency has been associated with an increasing number of clinical phenotypes that respond to CoQ(10) supplementation. In two siblings with encephalomyopathy, nephropathy and severe CoQ(10) deficiency, a homozygous mutation was identified in the CoQ(10) biosynthesis gene COQ2, encoding polyprenyl-pHB transferase. To confirm the pathogenicity of this mutation, we have demonstrated that human wild-type, but not mutant COQ2, functionally complements COQ2 defective yeast. In addition, an equivalent mutation introduced in the yeast COQ2 gene also decreases both CoQ(6) concentration and growth in respiratory-chain dependent medium. Polyprenyl-pHB transferase activity was 33-45% of controls in COQ2 mutant fibroblasts. CoQ-dependent mitochondrial complexes activities were restored in deficient fibroblasts by CoQ(10) supplementation, and growth rate was restored in these cells by either CoQ(10) or uridine supplementation. This work is the first direct demonstration of the pathogenicity of a COQ2 mutation involved in human disease, and establishes yeast as a useful model to study human CoQ(10) deficiency. Moreover, we demonstrate that CoQ(10) deficiency in addition to the bioenergetics defect also impairs de novo pyrimidine synthesis, which may contribute to the pathogenesis of the disease.

Oxidative stress, bioenergetics and neurodegenerative diseases

Neurodegenerative diseases (NDD) are an assortment of clinical central nervous system (CNS) disorders, characterized by intraneuronal accumulation of fibrillary material, forming intracellular aggregates. These abnormal products play a prominent role in the dysfunction and neuronal destruction that is specific for NDD, such as Alzheimer's, Parkinson's, and prion‐related diseases, known as transmissible spongiform encephalopathies. Related to this group are some neurological syndromes that involve muscle and CNS; Huntington's chorea, Friedreich's ataxia, and amyotrophic lateral sclerosis. A number of mechanisms appear to initiate or contribute to the neurodegenerative process, including oxidative stress, resulting from free radical generation and mitochondrial dysfunction. Overall, the clinical data on antioxidant efficacy tend to be encouraging. Moreover, the brain is highly dependent on energy availability, and mitochondrial functional impairment results in tissue injury, with detrimental clinical manifestations. Coenzyme Q (coenzyme Q10 in humans) is an essential component of the electron tranport chain in the mitochondria and the intracellular energy generation. It is also a potent antioxidant and a membrane stabilizer. For this reason, the use of coenzyme Q10 (and its derivative idebenone) in the prevention and treatment of NDD is fundamentally justified. Anecdotal, as well as preliminary results from well‐designed long‐term coenzyme Q10 clinical trials reinforce the validity of this novel approach. Due to the aging population, NDD have become a major health and social problem, and conceiving treatment or even arresting progression has become a primary focus of medical research worldwide.

Measurement and stability of plasma reduced, oxidized and total coenzyme Q10 in humans

There are findings indicating that a decreased ratio of plasma coenzyme Q10 (Q10) to LDL cholesterol could be associated with an increased risk of atherosclerosis. Furthermore, the proportion of plasma Q10H2 (reduced Q10, ubiquinol) of total Q10 has been shown to be attenuated in major diseases, such as hyperlipidemia and coronary artery disease. These observations suggest that measurement of plasma total Q10 and the proportion of plasma Q10H2 of total Q10 would be of clinical significance. However, epidemiological studies addressing this issue require large numbers of subjects, and measurements from unfrozen samples are unfeasible. For this reason, we evaluated the stability of Q10 samples during sample storage and processing. We also compared solid phase and hexane pre­treatments prior to high­performance liquid chromatographic determination of Q10. Our results indicate that samples for plasma total Q10 measurement can be pre­treated in normal laboratory lighting conditions, thawed and frozen several times, and stored deep frozen for a couple of years without changes in measured Q10 values. If purification of the samples by silica and C18 is needed, the best reproducibility tends to be achieved with powder treatment (not with cartridges). However, to measure successfully the proportion of plasma ubiquinol of total Q10, samples must be thawed, extracted, and analysed one at a time and quickly to ensure minimal ubiquinol oxidation during the measurement process.