Effect Of CoQ Research Articles

Abnormalities of lipid metabolism in neuronal models of CoQ10 deficiency (S49.004)

<h3>Objective:</h3> To investigate the role of lipid dysmetabolism in the neurological phenotype of primary and secondary CoQ₁₀ deficiencies. <h3>Background:</h3> CoQ₁₀ is a lipid molecule. Biosynthesis of CoQ₁₀ and cholesterol are linked via a common upstream pathway, specifically, the first enzyme of CoQ₁₀ biosynthesis, decaprenyl diphosphate synthase (PDSS1/PDSS2) utilizes geranylgeranyl-diphosphate (GGdP), a substrate generated by the mevalonate pathway, which is responsible for the <i>de novo</i> synthesis of cholesterol. Deficiency of CoQ₁₀ can be primary, due to a biosynthetic defect, or secondary to proteins not directly related to CoQ₁₀ biosynthesis. In both forms of CoQ₁₀ deficiency, there is clinical heterogeneity, but patients often present neurological conditions including Leigh syndrome and cerebellar ataxia. Phenotype variability might be due to molecular heterogenicity, multiple functions of CoQ₁₀, and/or tissue-specific mechanisms. The effects of CoQ₁₀ deficiency on lipid dysmetabolism in these diseases is unknown. <h3>Design/Methods:</h3> We used control and CoQ₁₀ deficient fibroblasts carrying mutations in PDSS2, COQ8A and APTX, to generate iPSCs, which were differentiated into neurons. To characterize lipid metabolism in the neurons, we performed lipidomics, transcriptional analyses, western blots, immunostaining, and biochemical and molecular assays. To characterize causal relationship between abnormal CoQ₁₀ and cholesterol metabolism, we pharmacologically manipulated the mevalonate pathway, and its CoQ₁₀ and cholesterol branches in SH-SY5Y neuronal lines. <h3>Results:</h3> Neurons with primary CoQ₁₀ deficiency showed significant impairment in fatty acids oxidation, sphingolipids biosynthesis, and cholesterol homeostasis, which were reproduced by inhibition of CoQ₁₀ deficiency in SH-SY5Y neurons. APTX mutant neurons, a model of secondary CoQ₁₀ deficiency, showed sphingolipids biosynthesis, and cholesterol homeostasis alterations, which were reproduced by inhibition of the mevalonate pathway in SH-SY5Y neurons. <h3>Conclusions:</h3> Primary and secondary forms of CoQ₁₀ deficiency are associated with alterations in lipid metabolism including cholesterol biosynthesis in neurons. <b>Disclosure:</b> Dr. Pesini Martin has nothing to disclose. Giacomo Monzio-Compagnoni has nothing to disclose. Miss Barriocanal has nothing to disclose. Dr. Hidalgo Gutierrez has received personal compensation for serving as an employee of Columbia University. Giulio Kleiner has nothing to disclose. Giussepe A Yanez has nothing to disclose. Mohamed Bakkali has nothing to disclose. Dr. Monfrini has nothing to disclose. Yashpal S Chhonker has nothing to disclose. Saba Tadesse has nothing to disclose. Dr. Larrea has nothing to disclose. Dr. Murry has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Finley law. Caterina Mariotti has nothing to disclose. Barbara Castellotti has nothing to disclose. Luis Lopez has nothing to disclose. Alessio Di Fonzo has nothing to disclose. Estela Area-Gomez has nothing to disclose. Catarina M Quinzii has nothing to disclose.

High-fat diet-induced met-hemoglobin formation in rats prone (WOKW) or resistant (DA) to the metabolic syndrome: effect of CoQ10 supplementation.

The aim of this study was to evaluate the effects of a high-fat diet (HFD) on oxidative indexes in WistarOttawaKarlsburg W (WOKW) rats used as a model of metabolic syndrome in comparison with Dark Agouti (DA) rats used as a control strain. This syndrome is defined by the occurrence of two or more risk factors including obesity, hypertension, dyslipidemia, and insulin resistance. Forty rats were used in the study and the effect of HFD was evaluated in terms of body weight and both hemoglobin and CoQ oxidative status. Moreover, 16 rats (8 of each strain) were supplemented with 3 mg/100 g b.w. of CoQ10 for 1 month in view of its beneficial properties in cardiovascular disease due to its antioxidant activity in the lipid environment. HFD promoted an increase in body weight, in particular in WOKW males, and in the methemoglobin (met-Hb) index in both strains. Moreover, HFD promoted endogenous CoQ10 oxidation. CoQ10 supplementation was able to efficiently counteract the HFD pro-oxidant effects, preventing met-Hb formation and CoQ oxidation.

Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment

Disorders of coenzyme Q(10) (CoQ(10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ(10) deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ(10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ(10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ(10) biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ(10)) decrease in neuronal CoQ(10) status (p < 0.01). Reduction of neuronal CoQ(10) status was accompanied by a progressive decrease in mitochondrial respiratory chain enzyme activities, with a 67.5 % decrease in cellular ATP production at 46 % residual CoQ(10). Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ(10). A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ(10) with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ(10) deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ(10) deficiency.

A Water Soluble CoQ10 Formulation Improves Intracellular Distribution and Promotes Mitochondrial Respiration in Cultured Cells

BackgroundMitochondria are both the cellular powerhouse and the major source of reactive oxygen species. Coenzyme Q10 plays a key role in mitochondrial energy production and is recognized as a powerful antioxidant. For these reasons it can be argued that higher mitochondrial ubiquinone levels may enhance the energy state and protect from oxidative stress. Despite the large number of clinical studies on the effect of CoQ10 supplementation, there are very few experimental data about the mitochondrial ubiquinone content and the cellular bioenergetic state after supplementation. Controversial clinical and in vitro results are mainly due to the high hydrophobicity of this compound, which reduces its bioavailability.Principal FindingsWe measured the cellular and mitochondrial ubiquinone content in two cell lines (T67 and H9c2) after supplementation with a hydrophilic CoQ10 formulation (Qter®) and native CoQ10. Our results show that the water soluble formulation is more efficient in increasing ubiquinone levels. We have evaluated the bioenergetics effect of ubiquinone treatment, demonstrating that intracellular CoQ10 content after Qter supplementation positively correlates with an improved mitochondrial functionality (increased oxygen consumption rate, transmembrane potential, ATP synthesis) and resistance to oxidative stress.ConclusionsThe improved cellular energy metabolism related to increased CoQ10 content represents a strong rationale for the clinical use of coenzyme Q10 and highlights the biological effects of Qter®, that make it the eligible CoQ10 formulation for the ubiquinone supplementation.

Mitochondrial dysfunction and Down's syndrome: Is there a role for coenzyme Q10?

Structural changes and abnormal function of mitochondria have been documented in Down's syndrome (DS) cells, patients, and animal models. DS cells in culture exhibit a wide array of functional mitochondrial abnormalities including reduced mitochondrial membrane potential, reduced ATP production, and decreased oxido-reductase activity. New research has also brought to central stage the prominent role of oxidative stress in this condition. This review focuses on recent advances in the field with a particular emphasis on novel translational approaches involving the utilization of coenzyme Q(10) (CoQ(10) ) to treat a variety of clinical phenotypes associated with DS that are linked to increased oxidative stress and energy deficits. CoQ(10) has already provided promising results in several different conditions associated with altered energy metabolism and oxidative stress in the CNS. Two studies conducted in Ancona investigated the effect of CoQ(10) treatment on DNA damage in DS patients. Although the effect of CoQ(10) was evidenced only at single cell level, the treatment affected the distribution of cells according to their content in oxidized bases. In fact, it produced a strong negative correlation linking cellular CoQ(10) content and the amount of oxidized purines. Results suggest that the effect of CoQ(10) treatment in DS not only reflects antioxidant efficacy, but likely modulates DNA repair mechanisms.

Biochemical rationale and experimental data on the antiaging properties of CoQ10 at skin level

Coenzyme Q(10) (CoQ(10) ) is a key component of the mitochondrial respiratory chain and, therefore, is essential for the bioenergetics of oxidative phosphorylation. It is also endowed with antioxidant properties, and recent studies pointed out its capability of affecting the expression of different genes. In this review, we analyze the data on the mechanisms by which CoQ(10) interacts with skin aging processes. The effect of CoQ(10) in preserving mitochondrial function cooperates in maintaining a proper energy level, which serves to prevent the aging skin from switching to anaerobic energy production mechanisms. Furthermore, the antioxidant capacity of CoQ(10) contributes to a positive effect against UV-mediated oxidative stress. Some of these effects have been assessed also in vivo, by the sensitive technique of ultraweak photoemission. Finally, CoQ(10) has been shown to influence, through a gene induction mechanism, the synthesis of some key proteins of the skin and to decrease the expression of some metalloproteinase such as collagenase. These mechanisms may also contribute to preserve collagen content of the skin.

Oral administration of coenzyme Q10 reduces MPTP-induced loss of dopaminergic nerve terminals in the striatum in mice

The neuroprotective effect of coenzyme Q(10) (CoQ(10)) has been reported in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. In this study, we investigated whether oral administration of CoQ(10) could protect the striatal dopaminergic (DAergic) nerve terminals against MPTP-induced toxicity in C57BL/6N mice using immunoisolation technique for DAergic synaptosomes. CoQ(10) significantly attenuated decrease in dopamine transporter as well as in synaptophysin and actin protein levels in DAergic synaptosomes from MPTP-treated mice. The effect of CoQ(10) was also observed in crude synaptosomes fraction, but not in homogenate. Our results indicate that the nerve terminals are a site for the action of CoQ(10) against the MPTP-induced DAergic neurodegeneration.

Ubiquinoneに関する薬理学的研究

The pharmacological activity of CoQ in relation to structure and the mechanism of potentiation in synaptic reflex were studied. 1. CoQ enhanced SR, eminently MSR, as contrasted to strychnine, in which PSR was dominant. 2. The effect of CoQ was dependent on the number of isoprenoid units, the more the numbers of isoprenoid units, the lower was the effective dose.