ubiquinone and beta-resorcylic-acid

Mutations in. To elucidate the ADCK4's function in podocytes, we generated a podocyte-specific,. Absence of. Our study shows that ADCK4 is required for CoQ

Topics: Animals; Enzyme Stability; Glomerulosclerosis, Focal Segmental; HEK293 Cells; Humans; Hydroxybenzoates; Methyltransferases; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Proteins; Podocytes; Protein Kinases; Ubiquinone

Topics: Humans; Hydroxybenzoates; Mitochondria; Nephrotic Syndrome; Podocytes; Steroids; Ubiquinone

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the

Topics: Animals; Brain; Disease Models, Animal; Energy Metabolism; Histocytochemistry; Hydroxybenzoates; Mice; Mitochondrial Encephalomyopathies; Neuroprotective Agents; Salicylic Acid; Survival Analysis; Treatment Outcome; Ubiquinone

Primary ubiquinone (co-enzyme Q) deficiency results in a wide range of clinical features due to mitochondrial dysfunction. Here, we analyse and characterize two mutations in the ubiquinone biosynthetic gene COQ7. One mutation from the only previously identified patient (V141E), and one (L111P) from a 6-year-old girl who presents with spasticity and bilateral sensorineural hearing loss. We used patient fibroblast cell lines and a heterologous expression system to show that both mutations lead to loss of protein stability and decreased levels of ubiquinone that correlate with the severity of mitochondrial dysfunction. The severity of L111P is enhanced by the particular COQ7 polymorphism (T103M) that the patient carries, but not by a mitochondrial DNA mutation (A1555G) that is also present in the patient and that has been linked to aminoglycoside-dependent hearing loss. We analysed treatment with the unnatural biosynthesis precursor 2,4-dihydroxybenzoate (DHB), which can restore ubiquinone synthesis in cells completely lacking the enzymatic activity of COQ7. We find that the treatment is not beneficial for every COQ7 mutation and its outcome depends on the extent of enzyme activity loss.

Topics: Animals; Base Sequence; Cell Line; Child; Consanguinity; Cytochrome P-450 Enzyme System; DNA Mutational Analysis; DNA, Mitochondrial; Female; Fibroblasts; Hearing Loss; Humans; Hydroxybenzoates; Membrane Proteins; Mice, Knockout; Mitochondrial Proteins; Mixed Function Oxygenases; Mutation; Spastic Paraplegia, Hereditary; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype-phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9(Q95X) and Coq9(R239X)), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9(R239X) mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. In contrast, Coq9(Q95X) mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9(R239X) mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype-phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.

Topics: Animals; Ataxia; Disease Models, Animal; Genetic Variation; Genotype; Hydroxybenzoates; Mammals; Mice; Mice, Transgenic; Mitochondrial Diseases; Muscle Weakness; Mutation, Missense; Ubiquinone

Coenzyme Q is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. Coenzyme Q deficiency has been associated with a range of metabolic diseases, as well as with some drug treatments and ageing.. We used whole exome sequencing (WES) to investigate patients with inherited metabolic diseases and applied a novel ultra-pressure liquid chromatography-mass spectrometry approach to measure coenzyme Q in patient samples.. We identified a homozygous missense mutation in the COQ7 gene in a patient with complex mitochondrial deficiency, resulting in severely reduced coenzyme Q levels We demonstrate that the coenzyme Q analogue 2,4-dihydroxybensoic acid (2,4DHB) was able to specifically bypass the COQ7 deficiency, increase cellular coenzyme Q levels and rescue the biochemical defect in patient fibroblasts.. We report the first patient with primary coenzyme Q deficiency due to a homozygous COQ7 mutation and a potentially beneficial treatment using 2,4DHB.

Topics: Amino Acid Sequence; Ataxia; Child; Child, Preschool; Chromatography, Liquid; DNA Mutational Analysis; Exome; Homozygote; Humans; Hydroxybenzoates; Infant, Newborn; Male; Mitochondria; Mitochondrial Diseases; Molecular Sequence Data; Muscle Weakness; Mutation, Missense; Sequence Alignment; Tandem Mass Spectrometry; Ubiquinone