Coenzyme Q10 Deficiency Research Articles

Lipidspeichermyopathien

Lipid storage myopathies are a clinically and genetically heterogeneous group of muscle diseases characterized by an accumulation of lipid in skeletal muscle. Currently four different groups of lipid storage myopathies are described: primary carnitine deficiency (PCD), multiple acyl-CoA dehydrogenase deficiency, primary and secondary coenzyme Q10 deficiency and neutral lipid storage diseases. It might be due to their rareness and considerable clinical variability that these disorders are frequently disregarded in neurological differential diagnosis. This article provides a synopsis of several new aspects of pathophysiology, symptoms, diagnostic tools and current therapeutic approaches of lipid storage myopathies.

Therapeutic use of coenzyme Q10 and coenzyme Q10-related compounds and formulations

Importance of the field: Coenzyme Q10 (CoQ10) is found in blood and in all organs. CoQ10 deficiencies are due to autosomal recessive mutations, ageing-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer and muscular and cardiovascular diseases have been associated with low CoQ10 levels, as well as different ataxias and encephalomyopathies.Areas covered in this review: We review the efficacy of a variety of commercial formulations which have been developed to solubilise CoQ10 and promote its better absorption in vivo, and its use in the therapy of pathologies associated with low CoQ10 levels, with emphasis in the results of the clinical trials. Also, we review the use of its analogues idebenone and MitoQ®.What the reader will gain: This review covers the most relevant aspects related with the therapeutic use of CoQ10, including existing formulations and their effects on its bioavailability.Take home message: CoQ10 does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption. Oral CoQ10 is a viable antioxidant strategy in many diseases, providing a significant to mild symptomatic benefit. Idebenone and MitoQ are promising substitutive CoQ10-related drugs which are well tolerated and safe.

Is there is Need for Ubiquinone (CoQ10) Supplementation in Statin- Associated Myopathy?

Statins are currently the most effective drugs in reducing low-density lipoprotein cholesterol (LDL-C). With their mechanism of action, by inhibiting 3-hydroxy-3 methylglutharyl coenzyme A reductase, statins decrease cholesterol production. The same biosynthetic pathway is shared by ubiquinone or coenzyme Q10. Statins block production of dekaprenyl-4-benzoate, a precursor of coenzyme Q10 (CoQ10), which is an essential component in mitochondrial transport system. Ubiquinone deficiency may affect oxidative phosphorylation and adenosine triphosphate production, which can subsequently result in impairing of muscle energy metabolism and contribute to development of myopathy. Statin therapy also decreases antioxidant status in the body, resulting in to increase in free radical damage to cells in various parts of body; liver, nerves, muscles. Statins can decrease natural antioxidant protection present in our body and predispose toxicity. Statin-associated myopathy is the most common side effect of statin treatment often lead to statin dose reduction, or therapy cessation, which can negatively affect cardiovascular risk management. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. Statins lower circulating levels of CoQ10 up to 54%, whereas several studies did not confirmed a lowering of CoQ10 levels in muscles during statin therapy and the evidence was given also on low dose of statin therapy, which did not appear to reduce intramuscular levels of CoQ10 in symptomatic patients with statin myopathy. The conflicting results have been published on the impaired mitochondrial function, which was found during the analysis of the myocyte cells in patients treated with statins. The supplementation of CoQ10 results in increasing of serum CoQ10, but it is not clear if it relieves myopatic symptoms in statin treated patients. Yet available intervention studies reported contrasting results and just two of them proved benefit of CoQ10 supplementation. Hence coenzyme Q10 supplementation is not currently recommended for routine use in the prophylaxis of statin toxicity.

The use of mitochondrial nutrients to improve the outcome of infertility treatment in older patients

We present a hypothesis emphasizing the role of mitochondrial dysfunction in reproductive senescence and suggesting the use of mitochondrial nutrients as an adjuvant treatment in older patients with infertility.

Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms

CoQ (coenzyme Q), an isoprenylated benzoquinone, is a well-known component of the electron-transfer system in eukaryotes. The main role of CoQ is to transfer electrons from NADH dehydrogenase and succinate dehydrogenase to CoQ:cytochrome c reductase in the respiratory chain. However, recent evidence indicates that an involvement in respiration is not the only role of CoQ. The second apparent role of CoQ is its anti-oxidation property, and other novel roles for CoQ, such as in disulfide-bond formation, sulfide oxidation and pyrimidine metabolism, have been reported. CoQ10, having ten isoprene units in the isoprenoid side chain, has been used as a medicine and is now commercially popular as a food supplement. Two yeast species, namely the budding yeast Saccharomyces cerevisiae, which produces CoQ6, and the fission yeast Schizosaccharomyces pombe, which produces CoQ10, are the main subjects of the present minireview because they have greatly contributed to our basic knowledge of CoQ biosynthesis among eukaryotes. The biosynthetic pathway that converts p-hydroxybenzoate into CoQ consists of eight steps in yeasts. The five enzymes involved in the biosynthetic pathway have been identified in both yeasts, yet the functions of three proteins were still not known. Analyses of the biosynthetic pathway in yeasts also contribute to the understanding of human genetic diseases related to CoQ deficiency. In the present minireview I focus on the biochemical and commercial aspects of CoQ in yeasts and in other organisms for comparison.

Nutrition and Heart Failure: Impact of Drug Therapies and Management Strategies

Nutrition impairment commonly occurs in patients with heart failure and affects disease progression. Vitamin and mineral deficiencies are associated with early mortality, particularly in patients classified as cachectic. Guideline-based therapies approved for heart failure, such as loop diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aldosterone antagonists, and beta-adrenergic blockers, can lead to electrolyte abnormalities and predispose to some vitamin and micronutrient deficits. Clinical trial evidence in support of supplementary vitamin and mineral therapies for heart failure patients is limited with the exception of documented calcium and possibly vitamin D, thiamine, and coenzyme Q10 deficiencies. This area is gaining significant attention, and research is ongoing. The clinician can help minimize morbidity from nutrition impairment through appropriate monitoring and correction of baseline and medication-induced electrolyte imbalances, in addition to vitamin and mineral supplementation when appropriate.

Coenzyme Q deficiency triggers mitochondria degradation by mitophagy

Coenzyme Q10 (CoQ) is a small lipophilic molecule critical for the transport of electrons from complexes I and II to complex III in the mitochondrial respiratory chain. CoQ deficiency is a rare human genetic condition that has been associated with a variety of clinical phenotypes. With the aim of elucidating how CoQ deficiency affects an organism, we have investigated the pathophysiologic processes present within fibroblasts derived from 4 patients with CoQ deficiency. Assays of cultured fibroblasts revealed decreased activities of complex II+III, complex III, and complex IV, reduced expression of mitochondrial proteins involved in oxidative phosphorylation, decreased mitochondrial membrane potential, increased production of reactive oxygen species (ROS), activation of mitochondrial permeability transition (MPT), and reduced growth rates. These abnormalities were partially restored by CoQ supplementation. Moreover, we demonstrate that CoQ deficient fibroblasts exhibited increased levels of lysosomal markers (β-galactosidase, cathepsin, LC3, and Lyso Tracker), and enhanced expression of autophagic genes at both transcriptional and translational levels, indicating the presence of autophagy. Electron microscopy studies confirmed a massive degradation of the altered mitochondria by mitophagy. Autophagy in CoQ deficient fibroblasts was abolished by antioxidants or cyclosporin treatments suggesting that both ROS and MPT participate in this process. Furthermore, prevention of autophagy in CoQ deficient fibroblasts by 3-methyl adenine or wortmannin, as well as the induction of CoQ deficiency in cells lacking autophagy (by means of genetic knockout of the Atg5 gene in mouse embryonic fibroblasts) resulted in apoptotic cell death, suggesting a protective role of autophagy in CoQ deficiency.

Hypotonia and Infantile Spasms: A New Phenotype of Coenzyme Q10 Deficiency?

Hypotonia and Infantile Spasms: A New Phenotype of Coenzyme Q₁₀ Deficiency?

How Can We Treat Mitochondrial Encephalomyopathies? Approaches to Therapy

Mitochondrial disorders are a heterogeneous group of diseases affecting different organs (brain, muscle, liver, and heart), and the severity of the disease is highly variable. The chronicity and heterogeneity, both clinically and genetically, means that many patients require surveillance follow-up over their lifetime, often involving multiple disciplines. Although our understanding of the genetic defects and their pathological impact underlying mitochondrial diseases has increased over the past decade, this has not been paralleled with regards to treatment. Currently, no definitive pharmacological treatment exists for patients with mitochondrial dysfunction, except for patients with primary deficiency of coenzyme Q10. Pharmacological and nonpharmacological treatments increasingly being investigated include ketogenic diet, exercise, and gene therapy. Management is aimed primarily at minimizing disability, preventing complications, and providing prognostic information and genetic counseling based on current best practice. Here, we evaluate therapies used previously and review current and future treatment modalities for both adults and children with mitochondrial disease.

Early Coenzyme Q10 Supplementation in Primary Coenzyme Q10 Deficiency

To the Editor: Primary coenzyme Q10 deficiency is considered to be the only treatable mitochondrial disorder, since patients have a response to oral coenzyme Q10 supplementation. The disease usually manifests with nephropathy and encephalomyopathy.1 It has been shown that oral coenzyme Q10 may stop the progression of encephalopathy, but no benefit from this therapy has been noted with respect to the evolution of renal disease associated with this deficiency.1,2 We now describe the results of long-term coenzyme Q10 supplementation in two patients with coenzyme Q10 deficiency caused by a homozygous missense mutation in the COQ2 gene.3,4 The clinical . . .

Functional characterization of human COQ4, a gene required for Coenzyme Q 10 biosynthesis

Defects in genes involved in coenzyme Q (CoQ) biosynthesis cause primary CoQ deficiency, a severe multisystem disorders presenting as progressive encephalomyopathy and nephropathy. The COQ4 gene encodes an essential factor for biosynthesis in Saccharomyces cerevisiae. We have identified and cloned its human ortholog, COQ4, which is located on chromosome 9q34.13, and is transcribed into a 795 base-pair open reading frame, encoding a 265 amino acid (aa) protein (Isoform 1) with a predicted N-terminal mitochondrial targeting sequence. It shares 39% identity and 55% similarity with the yeast protein. Coq4 protein has no known enzymatic function, but may be a core component of multisubunit complex required for CoQ biosynthesis. The human transcript is detected in Northern blots as a ∼1.4 kb single band and is expressed ubiquitously, but at high levels in liver, lung, and pancreas. Transcription initiates at multiple sites, located 333–23 nucleotides upstream of the ATG. A second group of transcripts originating inside intron 1 of the gene encodes a 241 aa protein, which lacks the mitochondrial targeting sequence (isoform 2). Expression of GFP-fusion proteins in HeLa cells confirmed that only isoform 1 is targeted to mitochondria. The functional significance of the second isoform is unknown. Human COQ4 isoform 1, expressed from a multicopy plasmid, efficiently restores both growth in glycerol, and CoQ content in COQ4 null yeast strains. Human COQ4 is an interesting candidate gene for patients with isolated CoQ 10 deficiency.

Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal Disease

Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2kd/kd genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2kd/kd mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2loxP/loxP knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2loxP/loxP knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment.

CABC1 Gene Mutations Cause Ubiquinone Deficiency with Cerebellar Ataxia and Seizures

Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q(10) deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.

Systematic evaluation of muscle coenzyme Q10 content in children with mitochondrial respiratory chain enzyme deficiencies

Coenzyme Q10 content, pathology evaluation, and electron transport chain (ETC) enzyme analysis were determined in muscle biopsy specimens of 82 children with suspected mitochondrial myopathy. Data were stratified into three groups: “probable” ETC defects, “possible” ETC defects, and disease controls. Muscle total, oxidized, and reduced coenzyme Q10 concentrations were significantly decreased in the probable defect group. Stepwise logistic regression indicated that only total coenzyme Q10 was significantly associated with probable ETC defect. Receiver operator characteristic (ROC) analysis suggested that total muscle coenzyme Q10 was the best predictor of an ETC complex abnormality. Determination of muscle coenzyme Q10 deficiency in children with suspected mitochondrial disease may facilitate diagnosis and encourage earlier supplementation of this agent.

Coenzyme Q10 deficiency with renal involvement: a newly characterized disorder

Coenzyme Q10 deficiency with renal involvement: a newly characterized disorder

Rapid neonatal weight gain in rats results in a renal ubiquinone (CoQ) deficiency associated with premature death

We have recently reported that maternal dietary imbalance during pregnancy and lactation can reduce the lifespan of offspring. Rats that were growth restricted in utero by maternal protein restriction and underwent rapid weight gain when suckled by control fed dams died earlier than animals whose mothers were fed a control diet throughout pregnancy and lactation. We demonstrate here that mitochondrial abnormalities and DNA damage occur in the kidney of offspring who die prematurely. We have established by direct measurement and by in vitro supplementation that mitochondrial abnormalities occur because of a functional deficit of the mitochondrial cofactor coenzyme Q9 (CoQ9). These data provide molecular insight into the association between maternal nutrition and determination of offspring lifespan, and identify, a potential dietary intervention to prevent detrimental consequences of imbalanced maternal nutrition.

COQ2 Nephropathy

Primary coenzyme Q(10) (CoQ(10)) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ(10) synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [II+III] and decreased CoQ(10) concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.

M.O.2 Mutations in the electron-transferring-flavoprotein dehydrogenase ( ETFDH) gene cause myopathic form of coenzyme Q10 deficiency

Coenzyme Q10 (CoQ10) deficiency has been identified in different clinical settings with various genetic background. We report patients having an isolated myopathic phenotype and mutations in a previously unreported gene to cause CoQ10 deficiency.

M.P.3.03 Treatment of myopathic form of coenzyme Q10 deficiency caused by electron-transferring-flavoprotein dehydrogenase ( ETFDH) gene mutations

Primary or secondary Coenzyme Q10 (CoQ10) deficiency in muscle has been demonstrated in various phenotypes and response to CoQ10 supplementation has shown benefit in most cases. We have recently identified a group of patients with isolated myopathic form of CoQ10 deficiency and mutations in electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. This gene is also responsible from glutaric aciduria type II (GAII), a disorder known for good response to riboflavin treatment. We discuss treatment strategy with CoQ10 and riboflavin in this disorder.

M.I.4 Primary and secondary coenzyme Q10 deficiency

Coenzyme Q10 (CoQ10) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions including the transport of electrons from mitochondrial respiratory chain complexes I and II to complex III. Deficiency of CoQ10 is an autosomal recessive syndrome with four major phenotypes: (1) encephalomyopathy characterized by the triad of recurrent myoglobinuria, brain involvement and ragged-red fibers; (2) severe infantile multisystemic disease; (3) cerebellar ataxia; and (4) isolated myopathy. The diversity of clinical presentations of CoQ10 deficiency suggests etiological heterogeneity, which has, in fact, been demonstrated by the identification of mutations in multiple genes. Mutations in the CoQ10 biosynthetic genes, PDSS1, PDSS2, and COQ2 have been identified in four families with infantile-onset disorders, predominantly encephalomyopathies with nephrotic syndrome. In addition, CoQ10 deficiency can be secondary as demonstrated by the association of APTX mutations, which cause ataxia oculomotor apraxia (AOA1) with deficiency of CoQ10 while mutations in electron-transferring flavoprotein dehydrogenase (ETF-DH) have been identified with the pure myopathic form of CoQ10 deficiency. Deficiency of CoQ10 is best detected in muscle biopsies or cultured fibroblasts, but blood levels of CoQ10 are not reliable to diagnose this condition. Defects of mitochondrial respiratory chain enzyme complexes I + III and II + III with normal activities of the individual enzymes is a clue to diagnose CoQ10 deficiency. Patients with all forms of CoQ10 deficiency have shown clinical improvements after initiating oral CoQ10 supplementation. Thus, early diagnosis is of critical importance in the management of these patients.