scholarly journals Coenzyme Q 10 and L-Carnitine Disturbances in Children with Mitochondrial Diseases

2020 ◽  
Author(s):  
Ekaterina A. Nikolaeva ◽  
Ilgar S. Mamedov ◽  
Irina V. Zolkina
Keyword(s):  
Coenzyme Q ◽  
Mitochondrial Diseases

scholarly journals Design of High-Throughput Screening of Natural Extracts to Identify Molecules Bypassing Primary Coenzyme Q Deficiency in Saccharomyces cerevisiae

2019 ◽  
Vol 25 (3) ◽  
pp. 299-309
Author(s):  
Aida M. Berenguel Hernández ◽  
Mercedes de la Cruz ◽  
María Alcázar-Fabra ◽  
Andrés Prieto-Rodríguez ◽  
Ana Sánchez-Cuesta ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Coenzyme Q ◽  
Genetic Disorders ◽  
Screening Method ◽  
Mitochondrial Diseases ◽  
Deficiency Syndrome ◽  
Natural Extracts ◽  
Representative Subset ◽  
Nonfermentable Carbon Source

Coenzyme Q10 (CoQ10) deficiency syndrome is a rare disease included in the family of mitochondrial diseases, which is a heterogeneous group of genetic disorders characterized by defective energy production. CoQ10 biosynthesis in humans requires at least 11 gene products acting in a multiprotein complex within mitochondria. The high-throughput screening (HTS) method based on the stabilization of the CoQ biosynthesis complex (Q-synthome) produced by the COQ8 gene overexpression is proven here to be a successful method for identifying new molecules from natural extracts that are able to bypass the CoQ6 deficiency in yeast mutant cells. The main features of the new approach are the combination of two yeast targets defective in genes with different functions on CoQ6 biosynthesis to secure the versatility of the molecule identified, the use of glycerol as a nonfermentable carbon source providing a wide growth window, and the stringent conditions required to mark an extract as positive. The application of this pilot approach to a representative subset of 1200 samples of the Library of Natural Products of Fundación MEDINA resulted in the finding of nine positive extracts. The fractionation of three of the nine extracts allowed the identification of five molecules; two of them are present in molecule databases of natural extracts and three are nondescribed molecules. The use of this screening method opens the possibility of discovering molecules with CoQ10-bypassing action useful as therapeutic agents to fight against mitochondrial diseases in human patients.

scholarly journals Modulating Mitophagy in Mitochondrial Disease

2019 ◽  
Vol 25 (40) ◽  
pp. 5597-5612 ◽  
Author(s):  
Eszter Dombi ◽  
Heather Mortiboys ◽  
Joanna Poulton
Keyword(s):  
Signaling Pathways ◽  
Mitochondrial Disease ◽  
Coenzyme Q ◽  
Mitochondrial Diseases ◽  
Degradation Pathway ◽  
Selective Degradation ◽  
Genes Encoding ◽  
Phosphoinositide 3 Kinase ◽  
Quality Control Mechanism ◽  
Amp Activated Protein Kinase

Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may affect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed the data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.

scholarly journals β-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1457
Author(s):  
Agustín Hidalgo-Gutiérrez ◽  
Eliana Barriocanal-Casado ◽  
María Elena Díaz-Casado ◽  
Pilar González-García ◽  
Riccardo Zenezini Chiozzi ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Coenzyme Q ◽  
Mitochondrial Diseases ◽  
The Elderly ◽  
Mitochondrial Metabolism ◽  
Cellular Mechanisms ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Long Term Treatment

Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remain challenging. Here, we show that beta-resorcylic acid (β-RA), which is a natural phenolic compound, competed in vivo with 4-hydroxybenzoic acid, which is the natural precursor of coenzyme Q biosynthesis. This led to a decrease in demethoxyubiquinone, which is an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, β-RA rescued the phenotype of Coq9R239X mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with β-RA also reduced the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to the prevention of hepatic steatosis and an increase in survival at the elderly stage of life. The reduction in WAT content was due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that β-RA acted through different cellular mechanisms, with effects on mitochondrial metabolism; as such, it may be used for the treatment of primary coenzyme Q deficiency, overweight, and hepatic steatosis.

scholarly journals β-RA targets mitochondrial metabolism and adipogenesis, leading to therapeutic benefits against CoQ deficiency and age-related overweight

2021 ◽  
Author(s):  
Agustín Hidalgo-Gutiérrez ◽  
Eliana Barriocanal-Casado ◽  
María Elena Díaz-Casado ◽  
Pilar González-García ◽  
Riccardo Zenezini Chiozzi ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Coenzyme Q ◽  
Mitochondrial Diseases ◽  
Term Treatment ◽  
Mitochondrial Metabolism ◽  
Cellular Mechanisms ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Long Term Treatment

AbstractPrimary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remains challenging. Here, we show that beta-resorcylic acid (β-RA), a natural phenolic compound, competes in vivo with 4-hydroxybenzoic acid, the natural precursor of Coenzyme Q biosynthesis. This leads to a decrease of demethoxyubiquinone, an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, β-RA rescues the phenotype of Coq9R239X mice, a model of primary mitochondrial encephalopathy. Moreover, we observe that long-term treatment with β-RA also reduces the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to a prevention of hepatic steatosis and an increase in survival at the old stage of life. The reduction in WAT content is due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and a stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that β-RA acts through different cellular mechanisms, with effects on mitochondrial metabolism, and it may be used for the treatment of primary Coenzyme Q deficiency, overweight, and hepatic steatosis.

scholarly journals Coenzyme Q at the Hinge of Health and Metabolic Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1785
Author(s):  
Juan Diego Hernández-Camacho ◽  
Laura García-Corzo ◽  
Daniel José Moreno Fernández-Ayala ◽  
Plácido Navas ◽  
Guillermo López-Lluch
Keyword(s):  
Oxidative Stress ◽  
Metabolic Diseases ◽  
Coenzyme Q ◽  
Redox Homeostasis ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Deficiency Syndrome ◽  
Plasma Lipoproteins ◽  
Mitochondrial Oxidative Stress ◽  
Key Factor

Coenzyme Q is a unique lipidic molecule highly conserved in evolution and essential to maintaining aerobic metabolism. It is endogenously synthesized in all cells by a very complex pathway involving a group of nuclear genes that share high homology among species. This pathway is tightly regulated at transcription and translation, but also by environment and energy requirements. Here, we review how coenzyme Q reacts within mitochondria to promote ATP synthesis and also integrates a plethora of metabolic pathways and regulates mitochondrial oxidative stress. Coenzyme Q is also located in all cellular membranes and plasma lipoproteins in which it exerts antioxidant function, and its reaction with different extramitochondrial oxidoreductases contributes to regulate the cellular redox homeostasis and cytosolic oxidative stress, providing a key factor in controlling various apoptosis mechanisms. Coenzyme Q levels can be decreased in humans by defects in the biosynthesis pathway or by mitochondrial or cytosolic dysfunctions, leading to a highly heterogeneous group of mitochondrial diseases included in the coenzyme Q deficiency syndrome. We also review the importance of coenzyme Q levels and its reactions involved in aging and age-associated metabolic disorders, and how the strategy of its supplementation has had benefits for combating these diseases and for physical performance in aging.

scholarly journals OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION

2020 ◽  
Vol 2 (338) ◽  
pp. 31-40
Author(s):  
B. A. Ussipbek ◽  
L. C. López ◽  
N. T. Ablaikhanova ◽  
M. K. Murzakhmetova
Keyword(s):  
Oxidative Stress ◽  
Free Radicals ◽  
Mitochondrial Dysfunction ◽  
Coenzyme Q10 ◽  
Mammalian Cells ◽  
Cell Damage ◽  
Coenzyme Q ◽  
Critical Role ◽  
Sulfide Oxidation ◽  
Mitochondrial Diseases

The process of cell damage resulting from the action of free radicals – reactive oxygen species (ROS) – is called oxidative stress. Most ROS are constantly formed in the cell – about 5 % of the oxygen consumed by tissues is converted into free radicals, but their level is normally so small that the cell inactivates them with the help of an antioxidant system. Different organs and tissues are exposed to different degrees of ROS and demonstrate different stability during the implementation of oxidative stress. The mechanisms of ROS formation by mitochondria under oxidative stress are still unclear. At the same time, it was found that mitochondrial dysfunction and the accumulation of mitochondrial mutations in tissues make a significant contribution to the aging process, as well as to the pathogenesis of a number of diseases characterized by neurodegeneration. Mutations lead to increased generation of free radicals, reduced ATP levels, and energy failure of cells. Coenzyme Q10 is a component of the mitochondrial respiratory chain. Violation of the biosynthesis of coenzyme Q10 can lead to a number of mitochondrial diseases. When coenzyme Q10 is deficient, sulfide metabolism plays a critical role. Sulfide metabolism in mammalian cells includes trans-sulfuration (biosynthetic) and hydrogen sulfide oxidation (H2S) (catabolic). Violation of H2S oxidation may contribute to oxidative stress in coenzyme Q deficiency or may play a synergistic role with oxidative stress in the pathogenesis of tissue specificity in coenzyme Q deficiency.

Arabidopsis 4-COUMAROYL-COA LIGASE 8 contributes to the biosynthesis of the benzenoid ring of coenzyme Q in peroxisomes

2019 ◽  
Vol 476 (22) ◽  
pp. 3521-3532
Author(s):  
Eric Soubeyrand ◽  
Megan Kelly ◽  
Shea A. Keene ◽  
Ann C. Bernert ◽  
Scott Latimer ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Time Course ◽  
Reverse Genetics ◽  
De Novo ◽  
Coenzyme Q ◽  
Control Level ◽  
Wild Type ◽  
Fluorescent Reporters ◽  
Coa Ligase ◽  
Peroxisomal Targeting

Plants have evolved the ability to derive the benzenoid moiety of the respiratory cofactor and antioxidant, ubiquinone (coenzyme Q), either from the β-oxidative metabolism of p-coumarate or from the peroxidative cleavage of kaempferol. Here, isotopic feeding assays, gene co-expression analysis and reverse genetics identified Arabidopsis 4-COUMARATE-COA LIGASE 8 (4-CL8; At5g38120) as a contributor to the β-oxidation of p-coumarate for ubiquinone biosynthesis. The enzyme is part of the same clade (V) of acyl-activating enzymes than At4g19010, a p-coumarate CoA ligase known to play a central role in the conversion of p-coumarate into 4-hydroxybenzoate. A 4-cl8 T-DNA knockout displayed a 20% decrease in ubiquinone content compared with wild-type plants, while 4-CL8 overexpression boosted ubiquinone content up to 150% of the control level. Similarly, the isotopic enrichment of ubiquinone's ring was decreased by 28% in the 4-cl8 knockout as compared with wild-type controls when Phe-[Ring-13C6] was fed to the plants. This metabolic blockage could be bypassed via the exogenous supply of 4-hydroxybenzoate, the product of p-coumarate β-oxidation. Arabidopsis 4-CL8 displays a canonical peroxisomal targeting sequence type 1, and confocal microscopy experiments using fused fluorescent reporters demonstrated that this enzyme is imported into peroxisomes. Time course feeding assays using Phe-[Ring-13C6] in a series of Arabidopsis single and double knockouts blocked in the β-oxidative metabolism of p-coumarate (4-cl8; at4g19010; at4g19010 × 4-cl8), flavonol biosynthesis (flavanone-3-hydroxylase), or both (at4g19010 × flavanone-3-hydroxylase) indicated that continuous high light treatments (500 µE m−2 s−1; 24 h) markedly stimulated the de novo biosynthesis of ubiquinone independently of kaempferol catabolism.

The Effect of Dietary Glutathione and Coenzyme Q10 on the Prevention and Treatment of Inflammatory Bowel Disease in Mice

2004 ◽  
Vol 74 (1) ◽  
pp. 74-85 ◽  
Author(s):  
Liu ◽  
Russell ◽  
Smith ◽  
Bronson ◽  
Milbury ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Dextran Sulfate ◽  
Coenzyme Q ◽  
Histological Evaluation ◽  
Therapeutic Effects ◽  
Prevention Study ◽  
Prevention And Treatment ◽  
Inflammatory Bowel ◽  
Pre Treatment

Because reactive oxygen species have been implicated as mediators of inflammatory bowel disease (IBD), we evaluated the potential preventive and therapeutic effects of two dietary antioxidants, glutathione (GSH) and coenzyme Q10 (CoQ10) on dextran sulfate sodium (DSS)-induced colitis in mice. Fifty female 8-wk old Swiss-Webster mice were randomly assigned to 4 groups for a pre-treatment 'prevention' study: (1) GSH (1% of diet); (2) CoQ10 (200 mg/kg/d); (3) DSS only (3% of drinking water); (4) control (no treatment). The mice in groups 1 and 2 were fed with GSH or CoQ10 for 21 wks, and the mice in groups 1, 2 and 3 were provided DSS from wk 7 for 4 cycles (1 cycle = 1 wk DSS followed by 2-wk water). Another 50 mice were randomly assigned to 4 groups for a 21-wk 'treatment' study where the mice in groups 1, 2, and 3 were administered DSS for 6 cycles (18 wks) to induce colitis. GSH and CoQ10 were added from wk 7 until the completion of the protocol. Loose stools and hemocult positivity were modestly but significantly reduced with GSH or CoQ10 at several periods during the intervention in both the prevention and treatment studies. In contrast, histological evaluation revealed increases in colonic dysplasia and ulceration with GSH or CoQ10. Thus, in this mouse model, GSH and CoQ10 appear to have a beneficial effect on acute signs of IBD, but may have an adverse impact on the chronic pathophysiology of the disease. Further studies using additional animal models are required to determine whether GSH or CoQ10 provide a favorable or unfavorable benefit:risk ratio in the prevention or treatment of IBD.

DIAGNOSTICS IN MITOCHONDRIAL DISEASES: THE NEED OF COLLABORATION BETWEEN CLINICIAN AND RESEARCH LABORATORIES

2006 ◽  
Vol 37 (S 1) ◽  
Author(s):  
R Van Coster ◽  
S Seneca ◽  
J Smet ◽  
W Lissens ◽  
J Jaeken ◽  
...  
Keyword(s):  
Mitochondrial Diseases
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