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Research Notes: Coenzyme Q-10 (CoQ10)Note: This page contains a collection of research abstracts and other materials about CoQ10. For the article about the use of CoQ10 for PWS, please see here. From Treatment of Mitochondrial Cytopathies Coenzyme Q10 (CoQ10), also known as ubiquinone, is a lipid soluble antioxidant that is synthesized from tyrosine and mevalonic acid by animal cells. Multiple vitamins and trace elements are required for its biosynthesis. Ubiquinones are components of all cell membranes, including mitochondrial membranes. Normal CoQ10 levels are maintained by endogenous synthesis and dietary sources, which include primarily animal products. This compound can also be administered as an exogenous supplement. Normal muscle mitochondria, blood, and fibroblast levels have been established at 1811 ± 99 ng/mg (n = 10), 637 ± 84 ng/mL (n = 8), and 48 ± 1.3 ng/mg (n = 5) respectively.[24] Ubiquinone also exists in a partially reduced form (ubisemiquinone) and a fully reduced form (ubiquinol). The role of CoQ10 in energy metabolism is well documented. Large amounts of CoQ10 are found in the mitochondrial inner membrane where it acts as a mobile electron carrier. Specifically, CoQ10 shuttles electrons from ETC complex I to complex III and from complex II to complex III. In addition, CoQ10 absorbs free radicals, which are probably generated to the greatest extent at the level of complex I, thereby acting as an antioxidant and preventing propagation of lipid peroxidation. CoQ10 also assists in regenerating active vitamin E from the tocopheroxyl radical. Deficient CoQ10 occurs in a wide range of human diseases and may occur due to insufficient dietary intake, impaired biosynthesis either due to endogenous causes or exogenous toxins, disproportionate utilization, or any combination of these. Given its hydrophobic nature and large particle size, oral administration results in inconsistent absorption, requiring oil-based liquid preparations or suspension in oil. Typical dosing begins at 4 mg per kg per day but may require dosages as high as 15 mg per kg per day to achieve clinical efficacy. CoQ10 is the most widely recognized supplement used in the treatment of mitochondrial cytopathies. Reported beneficial effects have included decrease in serum lactate, improved exercise tolerance, increased muscle strength, and magnetic resonance spectroscopy improvements. As a cellular antioxidant, its role is theoretically important, as free radical production is known to increase in mitochondrial disease. A number of primarily anecdotal reports suggest a favorable effect of CoQ10 in disorders of energy metabolism. A 17-year-old girl with MELAS had symptoms unresponsive to intravenous betamethasone, oral nicotinamide, oral CoQ10 (150 mg per day), and intravenous cytochrome c. Following initiation of CoQ10 at a dose of 300 mg per day she demonstrated improvement of her ophthalmologic symptoms, increased exercise tolerance, and decreased serum lactate (both before and after exercise).[25] A 19-year-old girl with Kearns-Sayre syndrome and low serum CoQ10 was treated with 120 mg per day of CoQ10. Serum CoQ10 increased to normal with concomitant lowering of fasting and postexercise lactate and improved ocular movements.[26] Seven patients with mitochondrial cytopathy and lactic acidosis were treated with 120 mg per day of CoQ10. Five of the seven patients had low serum CoQ10. Serum lactate following exercise was significantly diminished (P <0.05) in four of the patients. Monthly neurologic exams revealed improved muscle strength in all but one patient. No echocardiographic improvements were noted. There were no reported harmful side effects related to this treatment regimen.[27] Abe et al[28] reported on a patient with MELAS whose CSF lactate and pyruvate decreased, with noted improvement in seizures and myopathy following treatment with CoQ10. In a double-blinded placebo-controlled crossover trial of CoQ10 at 160 mg per day for 1 month, improved muscle strength and reduced fatigability were observed for those patients whose CoQ10 levels were lower than controls prior to initiation of treatment. Following 3 months of therapy, there was a statistically significant increase in overall muscle strength testing (P <0.05) but strength of specific proximal and distal musculature did not demonstrate significant improvement. The mean serum CoQ10 levels increased to above normal range within 2 months of treatment with no significant change thereafter. These investigators did not find any significant change in the metabolism of lactate while patients were on CoQ10. The global MRC score was the only significant improvement observed in this study.[29] Chan et al[30] sought to determine clinically valuable metabolic parameters of patients with mitochondrial encephalomyopathies treated with CoQ10 (150 mg per day) under exercise conditions. Nine patients were evaluated with bicycle ergometry prior to, during (3 months), and following treatment for 6 months. At rest, only two patients demonstrated elevated serum lactate levels, whereas, following exercise, seven patients had elevations of the same. In addition, the lactate-to-pyruvate ratio was abnormal at rest in eight patients and in all patients following exercise. At 3 months following onset of therapy, no clear change was noted in these biochemical parameters. At 6 months, however, there was a decrease in the lactate-to-pyruvate ratio at rest and in association with exercise (P <0.05 for male patients, n = 4) in six of the patients. There are several additional reports of patients who either showed equivocal changes or did not seem to demonstrate improvements while receiving CoQ10. In a multicenter trial, 44 patients with mitochondrial myopathy were treated for 6 months exclusively with CoQ10 at a dose of 2 mg per kg per day. Sixteen of the 44 patients showed a 25% decrease of postexercise lactate levels. All patients demonstrated statistically significant increases in muscle strength. These 16 patients were subsequently studied an additional 3 months in a blinded study of CoQ10 and placebo. Serum lactate levels were not further decreased in this time interval in those treated with CoQ10, although those receiving placebo developed worsening of postexercise lactate. Muscle strength did not improve during the second treatment period. No change was noted in terms of cardiac conduction abnormalities or ophthalmologic findings during the study period of 6 months.[31] Two patients with mitochondrial myopathies were treated for 1 year with either 100 mg or 50 mg daily of CoQ10. Neither of these patients had abnormal (low) CoQ10 levels. Following 1 year of treatment, neither patient demonstrated improvement of their ophthalmologic symptoms, quantitative isometric strength testing revealed no significant improvement, and CoQ10 levels remained essentially unchanged. It must be noted that the dose of administered CoQ10 in this study is less than is generally used to treat most adults.[32] Sixteen patients with varied mitochondrial cytopathies were treated with CoQ10 in addition to vitamins K3 and C, riboflavin, thiamine, and niacin. This open study, using 300 mg per day over a 2-month time period, did not show any benefit. The parameters evaluated included resting and postexercise serum lactate, phosphorous magnetic resonance spectroscopy, and regular follow-up of clinical symptoms.[33] The reliance on clinical and biochemical parameters exclusively in the evaluation of patients with mitochondrial cytopathies who undergo an experimental treatment may not provide an entirely accurate sense of effectiveness of therapy. [31] P magnetic resonance spectroscopy can be utilized to evaluate energy parameters in the specific tissue of interest, providing a noninvasive, quantitative measure of brain and/or muscle metabolism. In the presence of disordered mitochondrial metabolism one might expect to see a low concentration of phosphocreatine, a high concentration of inorganic phosphate, and a high calculated ADP.[34] Muscle can be evaluated at rest, during exercise, and during immediate postexercise recovery. In disorders of mitochondrial respiration, a decrease in the phosphocreatine/inorganic phosphate (PCr/Pi) ratio can be observed at rest. There is delayed replenishment of phosphocreatine following exercise. In some patients with mitochondrial cytopathy there may be no abnormality on 31P MRS, likely indicating that skeletal muscle mitochondria are not involved.[35] Again, with utilization of this technique, conflicting reports exist as to the effectiveness of CoQ10 therapy. Eight patients and 18 healthy controls were treated with 150 mg of CoQ10 per day for 6 months and evaluated by 31P MRS of the calf muscle at rest, during exercise, and during the postexercise recovery period. MRS was performed at the beginning of treatment and following 3 and 6 months of therapy. The mean PCr/Pi was significantly higher for controls prior to treatment and did not significantly change throughout the supplementation period. By 3 months of treatment, there was a nonsignificant repletion of phosphocreatine in the patient population. One patient had a dramatic improvement of the PCr/Pi at rest in addition to increased repletion of phosphocreatine postexercise following 3 months of treatment.[36] Barbiroli et al[37] utilized in vivo phosphorous magnetic resonance spectroscopy to evaluate the effectiveness of CoQ10 on improving brain and skeletal muscle mitochondrial respiration. Ten patients with mitochondrial cytopathies were evaluated by 31P MRS prior to and 6 months following treatment with 150 mg per day of CoQ10. There were 36 age-matched, healthy controls. Prior to treatment all patients demonstrated low concentrations of phosphocreatine and high ADP, indicative of mitochondrial dysfunction. There was a significant increased (P <0.02) brain concentration of phosphocreatine following treatment with CoQ10, in addition to a significant decrease (P <0.01) of brain concentration of inorganic phosphorous. With regards to the skeletal muscle evaluation, the 31P MRS spectra were not significantly different at rest either prior to or following treatment when compared with controls. Despite this, all patients did demonstrate a faster recovery of phosphocreatine following treatment and some (those with CPEO) reported increased strength. Two patients with mitochondrial encephalomyopathy were treated with 150 mg per day of CoQ10 and evaluated by bicycle ergometry and 31P nuclear magnetic resonance (NMR) spectroscopy prior to and 10 months after initiation of treatment. In both patients before treatment there was a low PCr/Pi at rest, in addition to a high resting serum lactate. Acidosis occurred during the exercise phase, followed by a delay in recovery after exercise. Furthermore, the bicycle ergometer test revealed a lowering of the ventilatory threshold as well as reduction of the maximum oxygen uptake. Pretreatment 31P NMR spectroscopy demonstrated the following abnormalities: twofold decrease of ATP concentration and abnormally low PCr/Pi ratio. Following 10 months of treatment, there was significant improvement during the exercise test along with a decrease in resting lactate, increase in oxygen consumption, increase in maximal load, and ventilatory threshold reached normal range. 31P NMR spectroscopy (performed on flexor digitorum superficialis muscle) corroborated these findings in that there was a significant increase from the baseline PCr/Pi ratio at rest in addition to improved recovery of all measured parameters. The decreased ATP concentration was still present, thought to a lesser degree. The postexercise PCr/Pi ratio was essentially unchanged for one patient but demonstrated a fourfold increase for the second patient. These results lend support to the efficacy of high-dose administration of CoQ10.[38] The literature suggests significant controversy regarding the efficacy of CoQ10 supplementation. Regardless, many patients report improved function, and the side effects associated with its use are rare. The majority of treating clinicians will administer a therapeutic trial in escalating doses (4 to 15 mg per kg per day) to determine its efficacy in an individual patient. Idebenone Idebenone is an analog of CoQ10 and acts both as a free radical scavenger as well as stimulating ATP formation by functioning as a mobile electron carrier. It is currently not available in the United States. A patient with LHON and myopathy was treated with oral idebenone (45 mg three times per day with increase by 135 mg per day every 2 days) following the onset of marked spasticity and weakness. By the sixth day of treatment (135 mg three times per day), the patient was able to walk, run, and climb stairs. On neurologic examination, there was marked reduction of spasticity of the lower extremities in addition to improved strength. Following observation of this improvement, idebenone was continued at a maximum of 405 mg per day for an additional 3 months, during which the patient remained clinically stable. Following withdrawal of idebenone, the patient again demonstrated weakness of the lower extremities and spastic paraparesis. Idebenone was reinitiated and within 2 weeks clinical improvement was again observed. This patient was additionally evaluated by brain and muscle 31P MRS. Following approximately 3 months of treatment there was an increase in phosphocreatine concentration and a decrease from baseline of inorganic phosphate toward reference values. When reimaged following withdrawal of idebenone, these parameters were markedly worsened and did not markedly improve following reinstitution of medication. In addition, 3 weeks following initiation of treatment, muscle studies showed an increased rate of recovery of phosphocreatine and inorganic phosphate. Though similar worsening of variables were observed following discontinuation of this medication, once resumed there was no return to the previously observed recovery levels.[39] A 10-year-old boy with LHON due to homoplasmic 11778 mutation was treated with oral idebenone (90 mg per day) after presenting with early-onset symptoms. After 7 months of treatment, visual acuity was improved slightly (6/90 bilaterally to 6/6).[40] However, spontaneous improvement in visual acuity is frequently reported in LHON. A patient with MELAS was treated with CoQ10 augmented by the addition of idebenone. Following 8 months of treatment with 210 mg per day of CoQ10, the patient demonstrated some improvement in terms of amelioration of sensory disturbance, ataxia, and muscle weakness. Serum lactate decreased slightly. Electroencephalogram (EEG) and Wechsler Adult Intelligence Scale (WAIS) testing remained unchanged when compared to prior to treatment. Motor and sensory conduction velocities normalized. Following the addition of 90 mg of idebenone, muscle strength improved further. Her EEG revealed marked improvement from baseline and from during treatment with CoQ10 alone. Her WAIS scores increased by 14 points. CSF protein decreased from 64 mg/dL to 45 mg/dL. The idebenone dose was then increased to 180 mg per day for an additional 11 months. CSF lactate decreased. The improvements were maintained for a follow-up time of 20 months.[41] The experience with idebenone may be too limited to draw any definitive conclusions. Further investigations may elucidate a role for this agent in a subset of patients with mitochondrial disease. Mitochondrion. 2007 Jun. The evidence supporting a treatment benefit for coenzyme Q10 (CoQ10) in primary mitochondrial disease (mitochondrial disease) whilst positive is limited. Mitochondrial disease in this context is defined as genetic disease causing an impairment in mitochondrial oxidative phosphorylation (OXPHOS). There are no treatment trials achieving the highest Level I evidence designation. Reasons for this include the relative rarity of mitochondrial disease, the heterogeneity of mitochondrial disease, the natural cofactor status and easy 'over the counter availability' of CoQ10 all of which make funding for the necessary large blinded clinical trials unlikely. At this time the best evidence for efficacy comes from controlled trials in common cardiovascular and neurodegenerative diseases with mitochondrial and OXPHOS dysfunction the etiology of which is most likely multifactorial with environmental factors playing on a background of genetic predisposition. There remain questions about dosing, bioavailability, tissue penetration and intracellular distribution of orally administered CoQ10, a compound which is endogenously produced within the mitochondria of all cells. In some mitochondrial diseases and other commoner disorders such as cardiac disease and Parkinson's disease low mitochondrial or tissue levels of CoQ10 have been demonstrated providing an obvious rationale for supplementation. This paper discusses the current state of the evidence supporting the use of CoQ10 in mitochondrial disease. Mitochondrion. 2007 Jun. Mevalonic aciduria (MVA) and phenylketonuria (PKU) are inborn errors of metabolism caused by deficiencies in the enzymes mevalonate kinase and phenylalanine 4-hydroxylase, respectively. Despite numerous studies the factors responsible for the pathogenicity of these disorders remain to be fully characterised. In common with MVA, a deficit in coenzyme Q(10) (CoQ(10)) concentration has been implicated in the pathophysiology of PKU. In MVA the decrease in CoQ(10) concentration may be attributed to a deficiency in mevalonate kinase, an enzyme common to both CoQ(10) and cholesterol synthesis. However, although dietary sources of cholesterol cannot be excluded, the low/normal cholesterol levels in MVA patients suggests that some other factor may also be contributing to the decrease in CoQ(10). The main factor associated with the low CoQ(10) level of PKU patients is purported to be the elevated phenylalanine level. Phenylalanine has been shown to inhibit the activities of both 3-hydroxy-3-methylglutaryl-CoA reductase and mevalonate-5-pyrophosphate decarboxylase, enzymes common to both cholesterol and CoQ(10) biosynthesis. Although evidence of a lowered plasma/serum CoQ(10) level has been reported in MVA and PKU, few studies have assessed the intracellular CoQ(10) concentration of patients. Plasma/serum CoQ(10) is influenced by dietary intake as well as its lipoprotein content and therefore may be limited as a means of assessing intracellular CoQ(10) concentration. Whether the pathogenesis of MVA and PKU are related to a loss of CoQ(10) has yet to be established and further studies are required to assess the intracellular CoQ(10) concentration of patients before this relationship can be confirmed or refuted. [Note: Plasma phenylalanine has been found to be elevated in some with PWS.] J Nutr Sci Vitaminol (Tokyo). 2007 Jun. PureSorb-Q40 (water-soluble type CoQ10 powder, CoQ10 content is 40 w/w%; hereinafter referred to as P40) is reported in the single-dose human and rat studies to have a greater absorption rate and absorbed volume of CoQ10 even taken postprandially, than those of regular CoQ10, which is lipid-soluble and generally taken in the form of soft-gel capsules. Thus, it was anticipated that the serum CoQ10 level might be higher with P40 tablets than with soft-gel capsules, even for the same dose of CoQ10. In the present study, in order to confirm the safety and measure the serum CoQ10 level for the case of an excessive dose of P40, a double-blinded Placebo controlled comparative study was conducted on 46 healthy volunteers and they were randomly divided into two groups. The P40 tablets or placebo were repeatedly taken by the volunteers. As the result of the study, for the group of taking 2250 mg/d of P40 (that is, 900 mg/d of CoQ10) for 4 consecutive wk, the serum CoQ10 level peaked at 2 wk after the start of intake at 8.79 +/- 3.34 microg/mL, and at 4 wk, it was at the level of 8.33 +/- 4.04 microg/mL. At 2 wk from withdrawal of intake, the serum CoQ10 level decreased to 1.30 +/- 0.49 microg/mL. The serum CoQ10 levels at these three points were significantly higher than those of the first day of intake and the Placebo group, which had no significant change throughout the study. Furthermore, P40 intake did not cause any significant changes in symptoms or clinical laboratory results as assessed by physical, hematological, blood biochemical or urinalysis tests. Physician examinations also did not reveal any abnormalities. These results confirm that P40 is an extremely safe material and it can produce better absorption of CoQ10. J Nutr Sci Vitaminol (Tokyo). 2007 Apr. Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant and essential component of the mitochondrial electron transfer system in the body, and is in wide use as a functional food material and cosmetic raw material. However, as CoQ10 is extremely lipid-soluble, absorption by the body is not easy. In general, people use soft-gel capsules in which CoQ10 is suspended in oil, and take these capsules with food. PureSorb-Q40 (P40) was developed to improve CoQ10 processability and absorption when taken without food, and the present study compared the effects of food on absorption between P40 and conventional lipid-soluble CoQ10 in rats and humans. The results of a rat study showed higher uptake when P40 was administered in the fasting state or with food compared to lipid-soluble CoQ10. The results of a human study showed that uptake was favorable when P40 was administered in the fasting state, and even when administered postprandially, a significant difference was noted in uptake rate up to 6 h after intake and uptake volume up to 8 h after intake when compared to lipid-soluble CoQ10. These results show that any CoQ10 product using P40 can be quickly and reliably absorbed by the body regardless of dosage form or intake time. Mitochondrion. 2007 Mar 16. Details of the discovery of ubiquinone (coenzyme Q) are described in the context of research on mitochondria in the early 1950s. The importance of the research environment created by David E. Green to the recognition of the compound and its role in mitochondria is emphasized as well as the dedicated work of Karl Folkers to find the medical and nutritional significance. The development of diverse functions of the quinone from electron carrier and proton carrier in mitochondria to proton transport in other membranes and uncoupling protein control as well as antioxidant and prooxidant functions is introduced. The successful application in medicine points the way for future development. Brain. 2007 Apr 5. Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with heterogenous phenotypic manifestations and genetic background. We describe seven patients from five independent families with an isolated myopathic phenotype of CoQ10 deficiency. The clinical, histological and biochemical presentation of our patients was very homogenous. All patients presented with exercise intolerance, fatigue, proximal myopathy and high serum CK. Muscle histology showed lipid accumulation and subtle signs of mitochondrial myopathy. Biochemical measurement of muscle homogenates showed severely decreased activities of respiratory chain complexes I and II + III, while complex IV (COX) was moderately decreased. CoQ10 was significantly decreased in the skeletal muscle of all patients. Tandem mass spectrometry detected multiple acyl-CoA deficiency, leading to the analysis of the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, previously shown to result in another metabolic disorder, glutaric aciduria type II (GAII). All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH deficiency leads to a secondary CoQ10 deficiency. Our results indicate that the late-onset form of GAII and the myopathic form of CoQ10 deficiency are allelic diseases. Since this condition is treatable, correct diagnosis is of the utmost importance and should be considered both in children and in adults. We suggest to give patients both CoQ10 and riboflavin supplementation, especially for long-term treatment. Mitochondrion. 2007 Mar 16. This review describes recent advances in our understanding of the uptake and distribution of coenzyme Q10 (CoQ10) in cells, animals, and humans. These advances have provided evidence of important pharmacokinetic factors, such as non-linear absorption and enterohepatic recirculation, and may facilitate the development of new CoQ10 formulations. Studies providing data which support the claim of tissue uptake of exogenous CoQ10 are also discussed. Improved CoQ10 dosing and drug level monitoring guidelines are suggested for adult and pediatric patient populations. Future CoQ10 research should consider uptake and distribution factors to determine cost-benefit relationships. J Biol Chem. 2007 Mar 16. MMitoQ10 is a ubiquinone that accumulates within mitochondria driven by a lipophilic triphenylphosphonium cation (TPP+). Once there MitoQ10 is reduced to its active ubiquinol and has been used to prevent mitochondrial oxidative damage. Here we show MitoQ10 is effectively reduced by complex II, but is a poor substrate for complex I, complex III and electron-transferring flavoprotein (ETF):quinone oxidoreductase (ETF-QOR). This differential reactivity could be explained if the bulky TPP+ moiety sterically hindered access of the ubiquinone group to enzyme active sites. Using molecular modelling and an uncharged analog of MitoQ10 with a sterically similar triphenylcarbon moiety (tritylQ10), we infer that the interaction of MitoQ10 with complex I and ETF-QOR, but not complex III, is inhibited by its bulky TPP+ moiety. To explain its lack of reactivity with complex III we show that the TPP+ moiety of MitoQ10 is ineffective at quenching pyrene fluorophors deeply buried within phospholipid bilayers and thus is positioned near the membrane surface. This superficial position of the TPP+ moiety suggests that the concentration of the entire MitoQ10 molecule in the membrane core is limited. As overlaying MitoQ10 onto the structure of complex III indicates that MitoQ10 cannot react with complex III without its TPP+ moiety entering the low dielectric of the membrane core, we conclude that the TPP+ moiety does anchor the tethered ubiquinol group out of reach of the active site(s) of complex III and this explains its slow oxidation. In contrast the ubiquinone moiety of MitoQ10 is able to quench fluorophors deep within the membrane core, indicating a high concentration of the ubiquinone moiety within the membrane and explaining its antioxidant efficacy. These findings significantly improve our understanding of TPP+-conjugated antioxidants and will facilitate the rational design of future mitochondria-targeted molecules. Muscle Nerve. 2007 Feb. Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q(10), and lipoic acid to target the above-mentioned cellular consequences) on several outcome variables using a randomized, double-blind, placebo-controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns-Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8-isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat-free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life. CNS Spectr. 2007 Jan. Coenzyme Q10 (CoQ10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals produced during oxidative phosphorylation in the inner mitochondrial membrane. Oxidative stress, resulting in glutathione loss and oxidative DNA and protein damage, has been implicated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Experimental studies in animal models suggest that CoQ10 may protect against neuronal damage that is produced by ischemia, atherosclerosis and toxic injury. Though most have tended to be pilot studies, there are published preliminary clinical trials showing that CoQ10 may offer promise in many brain disorders. For example, a 16-month randomized, placebo-controlled pilot trial in 80 subjects with mild Parkinson's disease found significant benefits for oral CoQ10 1,200 mg/day to slow functional deterioration. However, to date, there are no published clinical trials of CoQ10 in Alzheimer's disease. Available data suggests that oral CoQ10 seems to be relatively safe and tolerated across the range of 300-2,400 mg/day. Randomized controlled trials are warranted to confirm CoQ10's safety and promise as a clinically effective neuroprotectant. Muscle Nerve. 2006 Nov 1. Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q(10), and lipoic acid to target the above-mentioned cellular consequences) on several outcome variables using a randomized, double-blind, placebo-controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns-Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8-isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat-free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life. J Neurol Sci. 2006 Jul 15. Our aim was to report a new case with cerebellar ataxia associated with coenzyme Q10 (CoQ) deficiency, the biochemical findings caused by this deficiency and the response to CoQ supplementation. Patient: A 12-year-old girl presenting ataxia and cerebellar atrophy. Biochemical studies: Coenzyme Q10 in muscle was analysed by HPLC with electrochemical detection and mitochondrial respiratory chain (MRC) enzyme activities by spectrophotometric methods. CoQ biosynthesis in fibroblasts was assayed by studying the incorporation of radiolabeled 4-hydroxy[U 14C] benzoic acid by HPLC with radiometric detection. Results: Mitochondrial respiratory chain enzyme analysis showed a decrease in complex I + III and complex II + III activities. CoQ concentration in muscle was decreased (56 nmol/g of protein: reference values: 157-488 nmol/g protein). A reduced incorporation of radiolabeled 4-hydroxy[U- 14C] benzoic acid was observed in the patient (19% of incorporation respect to the median control values). After 16 months of CoQ supplementation, the patient is now able to walk unaided and cerebellar signs have disappeared. Conclusions: Cerebellar ataxia associated with CoQ deficiency in our case might be allocated in the transprenylation pathway or in the metabolic steps after condensation of 4-hydroxybenzoate and the prenyl side chain of CoQ. Clinical improvement after CoQ supplementation was remarkable, supporting the importance of an early diagnosis of this kind of disorders. Int J Biochem Cell Biol. 2005 Jun. Coenzyme Q10 is an essential cofactor in the electron transport chain and serves as an important antioxidant in both mitochondria and lipid membranes. CoQ10 is also an obligatory cofactor for the function of uncoupling proteins. Furthermore, dietary supplementation affecting CoQ10 levels has been shown in a number of organisms to cause multiple phenotypic effects. However, the molecular mechanisms to explain pleiotrophic effects of CoQ10 are not clear yet and it is likely that CoQ10 targets the expression of multiple genes. We therefore utilized gene expression profiling based on human oligonucleotide sequences to examine the expression in the human intestinal cell line CaCo-2 in relation to CoQ10 treatment. CoQ10 caused an increased expression of 694 genes at threshold-factor of 2.0 or more. Only one gene was down-regulated 1.5-2-fold. Real-time RT-PCR confirmed the differential expression for seven selected target genes. The identified genes encode proteins involved in cell signalling (n = 79), intermediary metabolism (n = 58), transport (n = 47), transcription control (n = 32), disease mutation (n = 24), phosphorylation (n = 19), embryonal development (n = 13) and binding (n = 9). In conclusion, these findings indicate a prominent role of CoQ10 as a potent gene regulator. The presently identified comprehensive list of genes regulated by CoQ10 may be used for further studies to identify the molecular mechanism of CoQ10 on gene expression. Regul Toxicol Pharmacol. 2006 Apr. The safety profile of Coenzyme Q10 (Kaneka Q10) at high doses for healthy subjects was assessed in a double-blind, randomized, placebo-controlled study. Kaneka Q10 in capsule form was taken for 4 weeks at doses of 300, 600, and 900 mg/day by a total of eighty-eight adult volunteers. No serious adverse events were observed in any group. Adverse events were reported in 16 volunteers with placebo, in 12 volunteers with the 300 mg dose, in 20 volunteers with the 600 mg, dose and in 16 volunteers with the 900 mg dose. The most commonly reported events included common cold symptoms and gastrointestinal effects such as abdominal pain and soft feces. These events exhibited no dose-dependency and were judged to have no relationship to Kaneka Q10. Changes observed in hematology, blood biochemistry, and urinalysis were not dose-related and were judged not to be clinically significant. The plasma CoQ10 concentration after 8-month withdrawal was almost the same as that before administration. These findings showed that Kaneka Q10 was well-tolerated and safe for healthy adults at intake of up to 900 mg/day. [Note: Up until a few years ago, Kaneka was the sole manufacturer of all of the CoQ10 on the global market and it is still the leading manufacturer. There are now about 5 companies in Japan, one in Taiwan and an undetermined number in China that manufacture CoQ10.] Neurology. 2006 Jan 24. Three unrelated, sporadic patients with muscle coenzyme Q10 (CoQ10) deficiency presented at 32, 29, and 6 years of age with proximal muscle weakness and elevated serum creatine kinase (CK) and lactate levels, but without myoglobinuria, ataxia, or seizures. Muscle biopsy showed lipid storage myopathy, combined deficiency of respiratory chain complexes I and III, and CoQ10 levels below 50% of normal. Oral high-dose CoQ10 supplementation improved muscle strength dramatically and normalized serum CK. Curr Opin Clin Nutr Metab Care. 2005 Nov. Purpose of Review: Coenzyme Q10 is administered for an ever-widening range of disorders, therefore it is timely to illustrate the latest findings with special emphasis on areas in which this therapeutic approach is completely new. These findings also give further insight into the biochemical mechanisms underlying clinical involvement of coenzyme Q10. Recent Findings: Cardiovascular properties of coenzyme Q10 have been further addressed, namely regarding myocardial protection during cardiac surgery, end-stage heart failure, pediatric cardiomyopathy and in cardiopulmonary resuscitation. The vascular aspects of coenzyme Q10 addressing the important field of endothelial function are briefly examined. The controversial issue of the statin/coenzyme Q10 relationship has been investigated in preliminary studies in which the two substances were administered simultaneously. Work on different neurological diseases, involving mitochondrial dysfunction and oxidative stress, highlights some of the neuroprotective mechanisms of coenzyme Q10. A 4-year follow-up on 10 Friedreich's Ataxia patients treated with coenzyme Q10 and vitamin E showed a substantial improvement in cardiac and skeletal muscle bioenergetics and heart function. Mitochondrial dysfunction likely plays a role in the pathophysiology of migraine as well as age-related macular degeneration and a therapy including coenzyme Q10 produced significant improvement. Finally, the effect of coenzyme Q10 was evaluated in the treatment of asthenozoospermia. Summary: The latest findings highlight the beneficial role of coenzyme Q10 as coadjuvant in the treatment of syndromes, characterized by impaired mitochondrial bioenergetics and increased oxidative stress, which have a high social impact. Besides their clinical significance, these data give further insight into the biochemical mechanisms of coenzyme Q10 activity. Neurobiol Dis. 2005 Apr. Neuronal cells depend on mitochondrial oxidative phosphorylation for most of their energy needs and therefore are at a particular risk for oxidative stress. Mitochondria play an important role in energy production and oxidative stress-induced apoptosis. In the present study, we have demonstrated that external oxidative stress induces mitochondrial dysfunction leading to increased ROS generation and ultimately apoptotic cell death in neuronal cells. Furthermore, we have investigated the role of Coenzyme Q10 as a neuroprotective agent. Coenzyme Q10 is a component of the mitochondrial respiratory chain and a potent anti-oxidant. Our results indicate that total cellular ROS generation was inhibited by Coenzyme Q10. Further, pre-treatment with Coenzyme Q10 maintained mitochondrial membrane potential during oxidative stress and reduced the amount of mitochondrial ROS generation. Our study suggests that water-soluble Coenzyme Q10 acts by stabilizing the mitochondrial membrane when neuronal cells are subjected to oxidative stress. Therefore, Coenzyme Q10 has the potential to be used as a therapeutic intervention for neurodegenerative diseases. Free Radic Biol Med. 2005 Mar 15. The main purpose of this study was to determine whether supplemental intake of coenzyme Q10 (CoQ) (ubiquinone-10) or alpha-tocopherol, either alone or together, could improve brain function of aged mice, as reflected in their cognitive or psychomotor performance. Separate groups of aged mice (24 months) were administered either CoQ (123 mg/kg/day), or alpha-tocopherol acetate (200 mg/kg/day), or both, or the vehicle (soybean oil) via gavage for a period of 14 weeks. Three weeks following the initiation of these treatments, mice were given a battery of age-sensitive behavioral tests for the assessment of learning, recent memory, and psychomotor function. In a test that required the mice to rapidly identify and remember the correct arm of a T-maze, and to respond preemptively in order to avoid an electric shock, the intake of alpha-tocopherol plus CoQ resulted in more rapid learning compared to the control group. Learning was not significantly improved in the mice receiving CoQ or alpha-tocopherol alone. None of the treatments resulted in a significant improvement of psychomotor performance in the old mice. In a separate study, treatment with higher doses of CoQ alone (250 or 500 mg/kg/day) for 14 weeks failed to produce effects comparable to those of the combination of alpha-tocopherol and CoQ. The apparent interaction of CoQ and alpha-tocopherol treatments is consistent with the previous suggestion, based on biochemical studies, that coenzyme Q and alpha-tocopherol act in concert. Overall, the findings suggest that concurrent supplementation of alpha-tocopherol with CoQ is more likely to be effective as a potential treatment for age-related learning deficits than supplementation with CoQ or alpha-tocopherol alone. Arch Neurol. 2005 Feb. Background: Primary coenzyme Q(10) (CoQ(10)) deficiency is rare. The encephalomyopathic form, described in few families, is characterized by exercise intolerance, recurrent myoglobinuria, developmental delay, ataxia, and seizures. Objective: To report a rare manifestation of CoQ(10) deficiency with isolated mitochondrial myopathy without central nervous system involvement. Methods: The patient was evaluated for progressive muscle weakness. Comprehensive clinical evaluation and muscle biopsy were performed for histopathologic analysis and mitochondrial DNA and respiratory chain enzyme studies. The patient began taking 150 mg/d of a CoQ(10) supplement. Results: The elevated creatine kinase and lactate levels with abnormal urine organic acid and acylcarnitine profiles in this patient suggested a mitochondrial disorder. Skeletal muscle histochemical evaluation revealed ragged red fibers, and respiratory chain enzyme analyses showed partial reductions in complex I, I + III, and II + III activities with greater than 200% of normal citrate synthase activity. The CoQ(10) concentration in skeletal muscle was 46% of the normal reference mean. The in vitro addition of 50 micromol/L of coenzyme Q(1) to the succinate cytochrome-c reductase assay of the patient's skeletal muscle whole homogenate increased the succinate cytochrome-c reductase activity 8-fold compared with 2.8-fold in the normal control homogenates. Follow-up of the patient in 6 months demonstrated significant clinical improvement with normalization of creatine kinase and lactate levels. Conclusions: The absence of central nervous system involvement and recurrent myoglobinuria expands the clinical phenotype of this treatable mitochondrial disorder. The complete recovery of myopathy with exogenous CoQ(10) supplementation observed in this patient highlights the importance of early identification and treatment of this genetic disorder. Biofactors. 2005. In previous works we have demonstrated plasma CoQ10 alterations in pituitary diseases, such as acromegaly or secondary hypothyroidism. However, pituitary lesions can induce complex clinical pictures due to alterations of different endocrine axes controlled by pituitary itself. A further rationale for studying CoQ10 in pituitary-adrenal diseases is related to the common biosynthetic pathway of cholesterol and ubiquinone. We have therefore assayed plasma CoQ10 levels in different conditions with increased or defective activity of pituitary-adrenal axis (3 subjects with ACTH-dependent adrenal hyperplasia, 2 cases of Cushing's disease and 1 case of 17-alpha-hydroxylase deficiency; 10 subjects with secondary hypoadrenalism, including three subjects with also secondary hypothyroidism). CoQ10 levels were significantly lower in isolated hypoadrenalism than in patients with adrenal hyperplasia and multiple pituitary deficiencies (mean +/- SEM: 0.57 +/- 0.04 vs 1.08 +/- 0.08 and 1.10 +/- 0.11 microg/ml, respectively); when corrected for cholesterol levels, the same trend was observed, but did not reach statistical significance. These preliminary data indicate that secretion of adrenal hormones is in some way related to CoQ10 levels, both in augmented and reduced conditions. However, since thyroid hormones have an important role in modulating CoQ10 levels and metabolism, when coexistent, thyroid deficiency seems to play a prevalent role in comparison with adrenal deficiency. [Note: A report on a case series of eight children and two adults with PWS with unexpected death or critical illness noted that below average sized adrenal glands were found in three children during autopsy, raising the possibility of unrecognized adrenal insufficiency in a subset of individuals with PWS.] Biofactors. 2005. Introduction: The effect of various dosages and dose strategies of oral coenzyme Q(10) (Q(100) administration on serum Q(10) concentration and bioequivalence of various formulations are not fully known. Subjects and Methods: In a randomized, double blind, placebo controlled trial 60 healthy men, aged 18-55 years, were supplemented with various dosages and dose strategies of coenzyme Q(10) soft oil capsules (Myoqinon 100 mg, Pharma Nord, Denmark) or crystalline 100 mg Q(10) powder capsules or placebo. After 20 days blood levels were compared and oxidative load parameters, malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS) were monitored to evaluate bioequivalence. All the subjects were advised to take the capsules with meals. Blood samples were collected after 12 hours of overnight fasting at baseline and after 20 days of Q(10) administration. Compliance was evaluated by counting the number of capsules returned by the subjects after the trial. Results: Compliance by capsule counting was >90%. Side effects were negligible. Serum concentrations of Q(10) (average for groups) increased significantly 3-10 fold in the intervention groups compared with the placebo group. Serum response was improved with a divided dose strategy. TBARS and MDA were in the normal ranges at baseline. After 20 days intervention in the 200 mg group TBARS and MDA decreased, but the decrease was only significant for MDA (Fig. 2). Conclusions: All supplementations increased serum levels of Q(10). Q(10) dissolved in an oil matrix was more effective than the same amount of crystalline Q(10) in raising Q(10) serum levels. 200 mg of oil/soft gel formulation of Q(10) caused a larger increase in Q(10) serum levels than did 100 mg. Divided dosages (2 x 100 mg) of Q(10) caused a larger increase in serum levels of Q(10) than a single dose of 200 mg. Supplementation was associated with decreased oxidative stress as measured by MDA-levels. Indians appear to have low baseline serum coenzyme Q(10) levels which may be due to vegetarian diets. Further studies in larger number of subjects would be necessary to confirm our findings. Clin Neuropharmacol. 2004 Jul-Aug. Mitochondrial encephalomyopathies encompass a group of disorders that have impaired oxidative metabolism in skeletal muscles and central nervous system. Many compounds have been used in clinical trials on mitochondrial diseases, but the outcomes have been variable. It remains controversial whether treatment of mitochondrial diseases with coenzyme Q 10 is effective. This paper describes a case of mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes, and exercise intolerance successfully treated with coenzyme Q 10. Efficacy of this therapy in this patient is correlated to control of lactic acidosis and serum creatine kinase levels. Disappointingly, larger studies with coenzyme Q 10 failed to demonstrate a clear beneficial effect on the entire study population with regard to clinical improvement or several parameters of the oxidative metabolism. They suggest that the use of coenzyme Q in treatment of mitochondrial diseases should be confined to protocols. There is a confounding variation in phenotype and genotype, and the natural history of the disorders in individual patients is not accurately predictable. The unpredictable a priori efficacy of therapy suggests that a long-term trial of oral coenzyme Q may be warranted. Am J Obstet Gynecol. 2004 May. Objective: Coenzyme Q10 is an antioxidant that may have a therapeutic role in cervical cancer. Study design: We investigated the cellular and molecular effects of 30 micromol/L Coenzyme Q10 in HeLa cells. Cell growth assays, fluorescence-activated cell sorting analyses, and Oil Red O staining were performed. Microarray experiments were performed in duplicate and analyzed on the basis of 2-fold changes in levels of gene expression. Results: Coenzyme Q10 inhibited cell growth and led to apoptosis. Microarray analysis showed that 264 sequences were altered over time, with enrichment in lipid-related genes. Enhanced lipid accumulation was confirmed with Oil Red O staining. Conclusion: A lipid response to Coenzyme Q10 may affect mechanisms of growth inhibition in HeLa cells. Mol Genet Metab. 2004 Apr. Marked progress has been made over the past 15 years in defining the specific biochemical defects and underlying molecular mechanisms of oxidative phosphorylation disorders, but limited information is currently available on the development and evaluation of effective treatment approaches. Metabolic therapies that have been reported to produce a positive effect include coenzyme Q(10) (ubiquinone), other antioxidants such as ascorbic acid and vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. The goal of these therapies is to increase mitochondrial ATP production, and to slow or arrest the progression of clinical symptoms. In the present study, we demonstrate for the first time that there is a significant increase in ATP synthetic capacity in lymphocytes from patients undergoing cofactor treatment. We also examined in vitro cofactor supplementation in control lymphocytes in order to determine the effect of the individual components of the cofactor treatment on ATP synthesis. A dose-dependent increase in ATP synthesis with CoQ(10) incubation was demonstrated, which supports the proposal that CoQ(10) may have a beneficial effect in the treatment of oxidative phosphorylation (OXPHOS) disorders. Neurology. 2004 Mar 9. Two brothers had late-onset progressive ataxia, cerebellar atrophy, and hypergonadotropic hypogonadism associated with coenzyme Q10 (CoQ10) deficiency in skeletal muscle. Both patients improved on high-dose CoQ10 supplementation, stressing the importance of CoQ10 deficiency in the differential diagnosis of cerebellar ataxia, even when onset is late. Arch Biochem Biophys. 2004 Mar 1. Coenzyme Q is both an essential electron carrier and an important antioxidant in the mitochondrial inner membrane. The reduced form, ubiquinol, decreases lipid peroxidation directly by acting as a chain breaking antioxidant and indirectly by recycling Vitamin E. The ubiquinone formed in preventing oxidative damage is reduced back to ubiquinol by the respiratory chain. As well as preventing lipid peroxidation, Coenzyme Q reacts with other reactive oxygen species, contributing to its effectiveness as an antioxidant. There is growing interest in using Coenzyme Q and related compounds therapeutically because mitochondrial oxidative damage contributes to degenerative diseases. Paradoxically, Coenzyme Q is also involved in superoxide production by the respiratory chain. To help understand how Coenzyme Q contributes to both mitochondrial oxidative damage and antioxidant defences, we have reviewed its antioxidant and prooxidant properties. Eur J Med Res. 2003 Nov 12. Background: Coenzyme Q10 (CoQ10) is frequently administered in mitochondrial diseases. Mitochondrial dysfunction and CoQ10 treatment was also proposed in neurodegenerative disorders as amyotrophic lateral sclerosis and Parkinsons disease. Patients and methods: Seventeen patients with mitochondrial CPEO were treated with CoQ10 (dosage: 0.60 1.80 mg/kg body wt) in an open trial. Serum levels of CoQ10 were monitored before and after 6-9 and 12-15 months of CoQ10 therapy. CoQ10 concentration in muscle was measured in all patients before treatment. Results: Prior to treatment CoQ10 concentration in muscle was normal in all patients. Eight patients completed the study after 12-15 months. Prior to treatment there was no correlation between CoQ10 in muscle and serum. There was no inverse correlation of serum lactate with CoQ10 in muscle before and in serum before and during therapy. CoQ10 serum level and body weight related CoQ10 dosage correlated significantly after 6-9 months but not after 12-15 months (p = 0.043 and n. s., respectively). During continued administration of CoQ10 the CoQ10 serum level was increased 2.76 +/- 1.00-fold after 6-9 months (range: 1.04-3.80). but returned to 1.70 +/- 0.98-fold after 12-15 months (range: 0.91-3.83). Serum lactate did not significantly change during treatment. There was no effect of CoQ10 treatment on signs and symptoms. Conclusion: The only transient increase of CoQ10 in serum has to be considered in any low dose long-term treatment with CoQ10. J Am Diet Assoc. 2003 Aug. Mitochondrial disorders are degenerative diseases characterized by a decrease in the ability of mitochondria to supply cellular energy requirements. Substantial progress has been made in defining the specific biochemical defects and underlying molecular mechanisms, but limited information is available about the development and evaluation of effective treatment approaches. The goal of nutritional cofactor therapy is to increase mitochondrial adenosine 5'-triphosphate production and slow or arrest the progression of clinical symptoms. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of antioxidants, electron transfer mediators (which bypass the defective site), and enzyme cofactors. Metabolic therapies that have been reported to produce a positive effect include Coenzyme Q(10) (ubiquinone); other antioxidants such as ascorbic acid, vitamin E, and lipoic acid; riboflavin; thiamin; niacin; vitamin K (phylloquinone and menadione); creatine; and carnitine. A literature review of the use of these supplements in mitochondrial disorders is presented. Am J Med Genet A. 2003 Jun 1. Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial respiratory chain and an important scavenger of reactive oxygen species. Low levels are found in individuals with reduced energy expenditure, cardiac and skeletal muscle dysfunction, and mitochondrial disorders, many of these manifestations are seen in individuals with Prader-Willi syndrome (PWS). In addition, CoQ10 supplementation frequently is given to individuals with this syndrome. To determine if CoQ10 levels are decreased in PWS, we studied plasma CoQ10 levels in 16 subjects with PWS, 13 with obesity of unknown cause, and 15 subjects without obesity but of similar age and compared with body composition. Plasma CoQ10 levels were significantly decreased (P < 0.05), using several statistical approaches in subjects with PWS (0.45 +/- 0.16 microg/ml), compared to subjects without obesity (0.93 +/- 0.56 microg/ml), but not different from subjects with obesity (0.73 +/- 0.53 microg/ml). When plasma CoQ10 was normalized relative to cholesterol, triglyceride, and creatinine levels and fat and lean mass [determined by dual energy X-ray absorptiometry (DEXA)] in the subjects with either PWS or obesity, no significant differences were observed. However, a lower muscle mass was found in the PWS subjects. Neurology. 2003 Apr 8. The authors measured coenzyme Q10 (CoQ10) concentration in muscle biopsies from 135 patients with genetically undefined cerebellar ataxia. Thirteen patients with childhood-onset ataxia and cerebellar atrophy had markedly decreased levels of CoQ10. Associated symptoms included seizures, developmental delay, mental retardation, and pyramidal signs. These findings confirm the existence of an ataxic presentation of CoQ10 deficiency, which may be responsive to CoQ10 supplementation. Arch Neurol. 2002 Oct. Background: Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression. Objective: To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD. Design: Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. Setting: Academic movement disorders clinics. Patients: Eighty subjects with early PD who did not require treatment for their disability. Interventions: Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d. Main Outcome Measure: The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. Results: The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was.09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P =.04). Conclusions: Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study. Free Radic Res. 2002 Apr. In this paper, we report results obtained from a continuing clinical trial on the effect of coenzyme Q10 (CoQ10) administration on human vastus lateralis (quadriceps) skeletal muscle. Muscle samples, obtained from aged individuals receiving placebo or CoQ10 supplementation (300mg per day for four weeks prior to hip replacement surgery) were analysed for changes in gene and protein expression and in muscle fibre type composition. Microarray analysis (Affymetrix U95A human oligonucleotide array) using a change in gene expression of 1.8-fold or greater as a cutoff point, demonstrated that a total of 115 genes were differentially expressed in six subject comparisons. In the CoQ10-treated subjects, 47 genes were up-regulated and 68 down-regulated in comparison with placebo-treated subjects. Restriction fragment differential display analysis showed that over 600 fragments were differentially expressed using a 2.0-fold or greater change in expression as a cutoff point. Proteome analysis revealed that, of the high abundance muscle proteins detected (2,086 +/- 115), the expression of 174 proteins was induced by CoQ10 while 77 proteins were repressed by CoQ10 supplementation. Muscle fibre types were also affected by CoQ10 treatment; CoQ10-treated individuals showed a lower proportion of type I (slow twitch) fibres and a higher proportion of type IIb (fast twitch) fibres, compared to age-matched placebo-treated subjects. The data suggests that CoQ10 treatment can act to influence the fibre type composition towards the fibre type profile generally found in younger individuals. Our results led us to the conclusion that coenzyme Q10 is a gene regulator and consequently has wide-ranging effects on over-all tissue metabolism. We develop a comprehensive hypothesis that CoQ10 plays a major role in the determination of membrane potential of many, if not all, sub-cellular membrane systems and that H2O2 arising from the activities of CoQ10 acts as a second messenger for the modulation of gene expression and cellular metabolism. Clin Biochem. 2002 Feb. OBJECTIVES: To investigate the ubiquinone-10 content in lymphocytes from phenylketonuric patients. DESIGN AND METHODS: We compared 23 patients with 25 age-matched controls. Ubiquinone-10 was analyzed by HPLC with electrochemical detection. RESULTS: Ubiquinone-10 concentrations were significantly lower in patients (77-270 nmol/g of protein) compared with controls (190-550) (p < 0.001). Significantly negative correlation was observed between ubiquinone-10 and phenylalanine (r = -0.441; p < 0.05). CONCLUSIONS: Ubiquinone-10 concentrations are decreased in lymphocytes from phenylketonuric patients. This deficiency is associated with high plasma phenylalanine concentrations. J Am Coll Nutr. 2001 Dec. Coenzyme Q is well defined as a crucial component of the oxidative phosphorylation process in mitochondria which converts the energy in carbohydrates and fatty acids into ATP to drive cellular machinery and synthesis. New roles for coenzyme Q in other cellular functions are only becoming recognized. The new aspects have developed from the recognition that coenzyme Q can undergo oxidation/reduction reactions in other cell membranes such as lysosomes, Golgi or plasma membranes. In mitochondria and lysosomes, coenzyme Q undergoes reduction/oxidation cycles during which it transfers protons across the membrane to form a proton gradient. The presence of high concentrations of quinol in all membranes provides a basis for antioxidant action either by direct reaction with radicals or by regeneration of tocopherol and ascorbate. Evidence for a function in redox control of cell signaling and gene expression is developing from studies on coenzyme Q stimulation of cell growth, inhibition of apoptosis, control of thiol groups, formation of hydrogen peroxide and control of membrane channels. Deficiency of coenzyme Q has been described based on failure of biosynthesis caused by gene mutation, inhibition of biosynthesis by HMG coA reductase inhibitors (statins) or for unknown reasons in ageing and cancer. Correction of deficiency requires supplementation with higher levels of coenzyme Q than are available in the diet. Lancet. 2000 Jul 29. Background: The respiratory-chain deficiencies are a broad group of largely untreatable diseases. Among them, coenzyme Q10 (ubiquinone) deficiency constitutes a subclass that deserves early and accurate diagnosis. Methods: We assessed respiratory-chain function in two siblings with severe encephalomyopathy and renal failure. We used high-performance liquid chromatography analyses, combined with radiolabelling experiments, to quantify cellular coenzyme Q10 content. Clinical follow-up and detailed biochemical investigations of respiratory chain activity were carried out over the 3 years of oral quinone administration. Findings: Deficiency of coenzyme Q10-dependent respiratory-chain activities was identified in muscle biopsy, circulating lymphocytes, and cultured skin fibroblasts. Undetectable coenzyme Q10 and results of radiolabelling experiments in cultured fibroblasts supported the diagnosis of widespread coenzyme Q10 deficiency. Stimulation of respiration and fibroblast enzyme activities by exogenous quinones in vitro prompted us to treat the patients with oral ubidecarenone (5 mg/kg daily), which resulted in a substantial improvement of their condition over 3 years of therapy. Interpretation: Particular attention should be paid to multiple quinone-responsive respiratory-chain enzyme deficiency because this rare disorder can be successfully treated by oral ubidecarenone. Free Radic Biol Med. 1999 Nov. Ubiquinol-10, the reduced form of coenzyme Q10, is a powerful antioxidant in plasma and lipoproteins. It has been suggested that endogenous ubiquinol-10 also exerts a protective role even towards DNA oxidation mediated by lipid peroxidation. Even though the antioxidant activity of coenzyme Q10 is mainly ascribed to ubiquinol-10, a role for ubiquinone-10 (the oxidized form), has been suggested not only if appropriate reducing systems are present. To investigate whether the concentration of ubiquinol-10 or ubiquinone-10 affects the extent of DNA damage induced by H2O2, we supplemented in vitro human lymphocytes with both forms of coenzyme Q10 and evaluated the DNA strand breaks by Comet assay. The exposure of lymphocytes to 100 microM H2O2 resulted in rapid decrease of cellular ubiquinol-10 content both in ubiquinol-10-enriched and in control cells, whereas alpha-tocopherol and beta-carotene concentration were unchanged. After 30 min from H2O2 exposure, the amount of DNA strand breaks was lower and cells' viability was significantly higher in ubiquinol-10-enriched cells compared with control cells. A similar trend was observed in ubiquinone-10-enriched lymphocytes when compared with control cells. Our experiments suggest that coenzyme Q10 in vitro supplementation enhances DNA resistance towards H2O2-induced oxidation, but it doesn't inhibit directly DNA strand break formation. Free Radic Biol Med. 1999 Jun. Coenzyme Q (CoQ) was previously demonstrated in vitro to indirectly act as an antioxidant in respiring mitochondria by regenerating alpha-tocopherol from its phenoxyl radical. The objective of this study was to determine whether CoQ has a similar sparing effect on alpha-tocopherol in vivo. Mice were administered CoQ10 (123 mg/kg/day) alone, or alpha-tocopherol (200 mg/kg/day) alone, or both, for 13 weeks, after which the amounts of CoQ10, CoQ9 and alpha-tocopherol were determined by HPLC in the serum as well as homogenates and mitochondria of liver, kidney, heart, upper hindlimb skeletal muscle and brain. Administration of CoQ10 and alpha-tocopherol, alone or together, increased the corresponding levels of CoQ10 and alpha-tocopherol in the serum. Supplementation with CoQ10 also elevated the amounts of the predominant homologue CoQ9 in the serum and the mitochondria. A notable effect of CoQ10 intake was the enhancement of alpha-tocopherol in mitochondria. Alpha-tocopherol administration resulted in an elevation of alpha-tocopherol content in the homogenates of nearly all tissues and their mitochondria. Results of this study thus indicate that relatively long-term administration of CoQ10 or alpha-tocopherol can result in an elevation of their concentrations in the tissues of the mouse. More importantly, CoQ10 intake has a sparing effect on alpha-tocopherol in mitochondria in vivo. J Cereb Blood Flow Metab. 1999 May. The authors studied, by in vivo phosphorus magnetic resonance spectroscopy (31P-MRS), the occipital lobes of 19 patients with mitochondrial cytopathies to clarify the functional relation between energy metabolism and concentration of cytosolic free magnesium. All patients displayed defective mitochondrial respiration with low phosphocreatine concentration [PCr] and high inorganic phosphate concentration [Pi] and [ADP]. Cytosolic free [Mg2+] and the readily available free energy (defined as the actual free energy released by the exoergonic reaction of ATP hydrolysis, i.e., deltaG(ATPhyd)) were abnormally low in all patients. Nine patients were treated with coenzyme Q10 (CoQ), which improved the efficiency of the respiratory chain, as shown by an increased [PCr], decreased [Pi] and [ADP], and increased availability of free energy (more negative value of deltaG(ATPhyd)). Treatment with CoQ also increased cytosolic free [Mg2+] in all treated patients. The authors findings demonstrate low brain free [Mg2+] in our patients and indicate that it resulted from failure of the respiratory chain. Free Mg2+ contributes to the absolute value of deltaG(ATPhyd). The results also are consistent with the view that cytosolic [Mg2+] is regulated in the intact brain cell to equilibrate, at least in part, any changes in rapidly available free energy. Biofactors. 1999. We used in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) to study the effect of CoQ10 on the efficiency of brain and skeletal muscle mitochondrial respiration in ten patients with mitochondrial cytopathies. Before CoQ, brain [PCr] was remarkably lower in patients than in controls, while [Pi] and [ADP] were higher. Brain cytosolic free [Mg2+] and delta G of ATP hydrolysis were also abnormal in all patients. MRS also revealed abnormal mitochondrial function in the skeletal muscles of all patients, as shown by a decreased rate of PCr recovery from exercise. After six-months of treatment with CoQ (150 mg/day), all brain MRS-measurable variables as well as the rate of muscle mitochondrial respiration were remarkably improved in all patients. These in vivo findings show that treatment with CoQ in patients with mitochondrial cytopathies improves mitochondrial respiration in both brain and skeletal muscles, and are consistent with Lenaz's view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit. Ann N Y Acad Sci. 1998 Nov 20. Ubiquinone (Q) shares its biological implication in membrane-associated redox reactions with a variety of other redox carriers, such as dehydrogenases, non-heme-iron proteins, and cytochromes. Peculiarities arise from the lack of transition metals, which in contrast to the other electron carriers do not participate in redox-shuttle activities of Q. Another peculiarity is the lipophilicity of Q, which allows free movement between reductants and oxidants of a membrane. The chemistry of Q reduction and ubiquinol oxidation requires the stepwise acceptance and transfer of two single electrons associated with the addition or release of two single H+. These special qualities are widely used in biological membranes for linear electron transfer and transmembranous H+ translocation. In mitochondria it was long reported that under certain conditions linear e- transfer from the semireduced form (SQ.) to native oxidants of the respiratory chain may run out of control, thereby establishing a permanent source of oxygen radical release. It should be mentioned that in mitochondria e- transfer to dioxygen out of sequence requires a particular treatment with inhibitors and uncouplers of the respiratory chain. Nevertheless, it is generally assumed that Q is mainly involved in mitochondrial O2.- generation and that mitochondria represent the major source of O2.- radicals under physiological and various pathophysiological conditions. The ever-increasing application of coenzyme Q as an antioxidant for the prophylaxis and treatment of a great variety of functional disorders, including senescence, has considerably stimulated our interest in the potential prooxidative potency of this natural electron carrier. Experimental evidence will be presented that under physiological conditions Q implicated in mitochondrial e- transfer of the respiratory chain is not involved in cellular oxygen activation. It will also be shown that alterations of Q from an e- carrier to an active radical promotor is possible under various conditions. In addition, reaction products emerging from the antioxidant activity of ubiquinol were found to stimulate the formation of inorganic as well as organic oxygen radicals. J Neurol Sci. 1998. We report severe coenzyme Q10 deficiency of muscle in a 4-year-old boy presenting with progressive muscle weakness, seizures, cerebellar syndrome, and a raised cerebro-spinal fluid lactate concentration. State-3 respiratory rates of muscle mitochondria with glutamate, pyruvate, palmitoylcarnitine, and succinate as respiratory substrates were markedly reduced, whereas ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine were oxidized normally. The activities of complexes I, II, III and IV of the electron transport chain were normal, but the activities of complexes I+III and II+III, both systems requiring coenzyme Q10 as an electron carrier, were dramatically decreased. These results suggested a defect in the mitochondrial coenzyme Q10 content. This was confirmed by the direct assessment of coenzyme Q10 level by high-performance liquid chromatography in patient's muscle homogenate and isolated mitochondria, revealing levels of 16% and 6% of the control values, respectively. We did not find any impairment of the respiratory chain either in a lymphoblastoid cell line or in skin cultured fibroblasts from the patient, suggesting that the coenzyme Q10 depletion was tissue-specific. This is a new case of a muscle deficiency of mitochondrial coenzyme Q in a patient suffering from an encephalomyopathy. Cell Mol Biol (Noisy-le-grand). 1997 Jul. With phosphorus magnetic resonance spectroscopy (31P-MRS) we studied in vivo the effect of six-month coenzyme Q10 treatment on the efficiency of brain and skeletal muscle mitochondrial respiration in six patients with different mitochondrial cytopathies. Before CoQ we found a low phosphocreatine content (average of 25% decrease from controls) in the occipital lobes of all patients. Calculated [ADP] and the relative rate of ATP synthesis were high (as an average, 57% and 16% above control group respectively), whereas the cytosolic phosphorylation potential was low (as an average, 60% of control value). 31P-MRS also revealed an average of 29% reduction of the mitochondrial function in the skeletal muscle of patients compared with controls. After a six-month treatment with 150 mg CoQ10/day all brain variables were remarkably improved in all patients, returning within the control range in all cases. Treatment with CoQ also improved the muscle mitochondrial functionality enough to reduce the average deficit to 56% of the control group. These in vivo findings show the beneficial effect of CoQ in patients with mitochondrial cytopathies, and are consistent with the view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit. Mol Aspects Med. 1997. The effects of oral supplementation of 100 mg coenzyme Q10 (CoQ10) for 6 months on muscle energy metabolism during exercise and recovery were evaluated in middle-aged post-polio (n = 3) and healthy subjects (n = 4) by the use of phosphorus-31 nuclear magnetic resonance spectroscopy. The metabolic response to isometric plantar flexion at 60% of maximal voluntary contraction force (MVC) for 1.5 min was determined in gastrocnemius muscles before, after 3- (3MO) and 6-month (6MO) of CoQ10 supplementation. The MVC of plantar flexion was unchanged following CoQ10 supplementation. The resting Pi/PCr ratio in gastrocnemius muscles of all subjects decreased after 3MO- and 6MO-CoQ10 (P < 0.05). The post-polio individuals showed a progressive decrease in this ratio, while less pronounced changes were observed in the control subjects. Similarly, the post-polio individuals showed a lower Pi/PCr ratio at the end of 60% MVC in both 3MO- and 6MO-CoQ10, whereas no change in the ratio was observed in the control subjects. A less pronounced decrease in muscle pH was observed at the end of 60% MVC in both 3MO- and 6MO-CoQ10 in the post-polio individuals, but not in the control subjects. No systematic difference in end-exercise ATP was observed between the three phases in both groups. The half-time of recovery for PCr decreased in all subjects after 6MO-CoQ10 supplementation (P < 0.05). The results suggest that CoQ10 supplementation affects muscle energy metabolism in post-polio individuals to a greater extent than in control subjects. The mechanism for this effect is not clear, but may involve an effect of CoQ10 on peripheral circulation in the calf muscles, its action in mitochondrial oxidative phosphorylation and/or its antioxidant potential. Eur Neurol. 1997. We report a short-term double-blind, crossover study of CoQ10 in 8 patients with mitochondrial encephalomyopathies. Four patients had myoclonus epilepsy with ragged-red fibers syndrome, 3 had mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome, and 1 had chronic progressive external ophthalmoplegia with myopathy. A trend of effectiveness of CoQ10 in several parameters was noted. Fatigability of daily activities was alleviated. The endurance to muscle exercise was augmented. Global muscle strength scored by Medical Research Council scale was increased. The extent of elevation in serum lactate and pyruvate levels after exercise was decreased. However, only the global MRC index score had a statistical significance (p < 0.05). There were no side effects during therapy. The serum CoQ10 levels were significantly lower in patients than in normal controls before CoQ10 treatment and increased significantly after treatment. Biochem Biophys Res Commun. 1996 Jul 16. In the human, coenzyme Q10 (vitamin Q10) is biosynthesized from tyrosine through a cascade of eight aromatic precursors. These precursors indispensably require eight vitamins, which are tetrahydrobiopterin, vitamins B6, C, B2, B12, folic acid, niacin, and pantothenic acid as their coenzymes. Three of these eight vitamins (the coenzyme B6, and the coenzymes niacin and folic acid) are indispensable in the biosynthesis of the four bases (thymidine, guanine, adenine, and cytosine) of DNA. One or more of the three vitamins required for DNA are known to cause abnormal pairing of the four bases, which can then result in mutations and the diversity of cancer. The coenzyme B6, required for the conversion of tyrosine to p-hydroxybenzoic acid, is the first coenzyme required in the cascade of precursors. A deficiency of the coenzyme B6 can cause dysfunctions, prior to the formation of vitamin Q10, to DNA. Former data on blood levels of Q10 and new data herein on blood levels of B6, measured as EDTA, in cancer patients established deficiencies of Q10 and B6 in cancer. This complete biochemistry relating to biosyntheses of Q10 and the DNA bases is a rationale for the therapy of cancer with Q10 and other entities in this biochemistry. Eur Neurol. 1996. 31P magnetic resonance spectroscopy (MRS) was used to study an open therapeutic trial of coenzyme Q10 (CoQ) in mitochondrial encephalomyopathies. Eight patients were treated with 150 mg CoQ per day for 6 months. 31P MRS spectra of calf muscle were recorded at rest, during exercise and in the immediate postexercise recovery period. Although there was an improvement of the mean ratio of phosphocreatine (PCr) to inorganic phosphate during the post-exercise recovery period after 3 months of treatment, this finding was mainly due to a single therapy responder and did not reflect a beneficial effect on the whole group. Improved repletion of PCr persisted after 6 months of therapy. Our study identified a single responder to this therapy, whose response could not be predicted on the basis of clinical, biochemical or molecular data. These findings suggest that therapeutic trials of CoQ should be performed under close metabolic monitoring in order both to identify responders for subsequent long-term treatment and to evaluate possible mechanisms of this supportive therapy. J Thorac Cardiovasc Surg. 1995 Oct. Coenzyme Q10 (CoQ10) is a natural mitochondrial respiratory chain constituent with antioxidant properties. This study tests the hypothesis that CoQ10 administered before the onset of reoxygenation on cardiopulmonary bypass, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass. The antioxidant properties of CoQ10 were confirmed by an in vitro study in which normal myocardial homogenates were incubated with the oxidant, t-butylhydroperoxide. Fifteen immature piglets (< 3 weeks old) were placed on 60 minutes of cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (oxygen tension about 400 mm Hg). Ten others became hypoxemic on cardiopulmonary bypass for 30 minutes by lowering oxygen tension to approximately 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 30 minutes. In five piglets, CoQ10 (45 mg/kg) was added to the cardiopulmonary bypass circuit 15 minutes before reoxygenation, and five others were not treated (no treatment). Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance (conductance catheter), oxidant damage (lipid peroxidation) was assessed by measuring conjugated diene levels in coronary sinus blood, and antioxidant reserve capacity was determined by measuring malondialdehyde in myocardium after cardiopulmonary bypass incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant damage and allowed complete functional recovery. Reoxygenated hearts (no treatment) showed a progressive increase in conjugated diene levels in coronary sinus blood after reoxygenation (2.3 +/- 0.6 A233 nm/0.5 ml plasma at 30 minutes after reoxygenation) and reduced antioxidant reserve capacity (malondialdehyde: 1219 +/- 157 nmol/g protein at 4.0 mmol/L t-butylhydroperoxide), resulting in severe postbypass dysfunction (percent end-systolic elastance = 38 +/- 6). Conversely, CoQ10 treatment avoided the increase in conjugated diene levels (2.1 +/- 0.6 vs 1.1 +/- 0.3, p < 0.05 vs no treatment), retained normal antioxidant reserve (896 +/- 76 nmol/g protein, p < 0.05 vs no treatment), and allowed nearly complete recovery of function (94% +/- 7%, p < 0.05 vs no treatment). We conclude that reoxygenation of the hypoxemic immature heart on cardiopulmonary bypass causes oxygen-mediated myocardial injury, which can be limited by CoQ10 treatment before reoxygenation. These findings imply that coenzyme Q10 can be used to surgical advantage in cyanotic patients, because therapeutic blood levels can be achieved by preoperative oral administration of this approved drug. Mol Aspects Med. 1994. Phosphorus magnetic resonance spectroscopy (31P-MRS) has emerged as a noninvasive reliable tool for in vivo study of human tissue bioenergetics. It detects and quantifies some phosphorylated compounds present in millimolar concentration inside the cell, including ATP, phosphocreatine (PCr) and inorganic phosphate (Pi). By 31P-MRS we studied brain and skeletal muscle energy metabolism of three patients with retinitis pigmentosa before and after oral coenzyme Q10 (CoQ10) (100 mg/day). Before treatment we found a low PCr content in the brains of all patients, accompanied by a high [Pi] and high [ADP]. In two of three patients CoQ10 treatment resulted in a larger brain energy reserve mainly shown by an increased [PCr]. Abnormal muscle mitochondrial function was found only in one patient as shown by a reduced rate of PCr resynthesis after exercise. In this patient CoQ10 treatment resulted in an increased rate of PCr resynthesis. Our observations indicate that CoQ10 can improve mitochondrial functionality in the brain and skeletal muscle of patients with retinitis pigmentosa. J Clin Pharmacol. 1993 Mar. Inhibitors of HMG-CoA reductase are new safe and effective cholesterol-lowering agents. Elevation of alanine-amino transferase (ALT) and aspartate-amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG-CoA reductase affects also the biosynthesis of ubiquinone (CoQ10). We studied two groups of five healthy volunteers treated with 20 mg/day of pravastatin (Squibb, Italy) or simvastatin (MSD) for a month. Then we treated 30 hypercholesterolemic patients in a double-blind controlled study with pravastatin, simvastatin (20 mg/day), or placebo for 3 months. At the beginning, and 3 months thereafter we measured plasma total cholesterol, CoQ10, ALT, AST, CK, and other parameters (urea, creatinine, uric acid, total bilirubin, gamma GT, total protein). Significant changes in the healthy volunteer group were detected for total cholesterol and CoQ10 levels, which underwent about a 40% reduction after the treatment. The same extent of reduction, compared with placebo was measured in hypercholesterolemic patients treated with pravastatin or simvastatin. Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage. Neurology. 1992 Jun. Two patients with mitochondrial encephalomyopathy due to complexes I and IV deficiencies received 150 mg/d of coenzyme Q10 (CoQ). We studied them with a bicycle ergometer exercise test and 31P NMR spectroscopy before and after 10 months of treatment. Before treatment, we observed a low phosphocreatine/inorganic phosphate (PCr/P(i)) resting value along with abnormally high resting lactate concentration. During exercise, there was a pronounced acidosis with delayed kinetics of postexercise recovery for blood lactate, pH, PCr, and PCr/P(i) ratio. Oxygen uptake during exercise was reduced while the lowering of the ventilatory threshold indicated an early activation of glycolysis. After treatment, the bicycle ergometer exercise test indicated a significant improvement with a decrease in resting blood lactate level, an increase in oxygen consumption during exercise, and an increase in the kinetics of lactate disappearance during the recovery period. A shift of the ventilatory threshold to higher workload was present. 31P NMR spectroscopy confirmed the improvement, showing a significant increase in the PCr/P(i) ratio at rest and in the kinetics of recovery for pH, PCr, and PCr/P(i) ratio following exercise in patient 1. For patient 2, we observed a less pronounced acidosis correlated with a lesser amount of Pi produced during exercise. These observations indicate an improvement of mitochondrial function and a shift from high to low glycolytic activity in both patients consequent to CoQ treatment. Acta Neurol Scand. 1991 Jun. Many CoQ trials for |