Hidalgo-Gutierrez 2015 Abstract MiP2015
|Strategies to enhance the endogenous biosynthesis of Coenzyme Q.|
Primary CoQ10 deficiency is a rare mitochondrial disease caused by mutations in CoQ biosynthetic genes. This syndrome is associated to five major clinical presentations: 1) encephalomyopathy, 2) severe infantile multisystemic disease, 3) cerebellar ataxia, 4) isolated myopathy, and 5) steroid-resistant nephrotic syndrome . The only therapeutic option available for CoQ10 deficiency syndrome is the exogenous CoQ10 supplementation. However, the results of this therapy are poor in patients with neurologic symptoms due to low absorption and bioavailability of exogenous CoQ10 . In those cases, the stimulation of endogenous CoQ10 biosynthesis could be an alternative and effective therapeutic option . To do that, it is theoretically possible to bypass the defect in a biochemical pathway providing a metabolic intermediate that is downstream to the defective site. Thus, if the defect is in the Coq9 gene, we could assess the ability of 2,4-dihydroxibenzoic acid (2,4-diHB) to rescue CoQ deficiency. Accordingly, we have treated COQ9R244X human fibroblasts with 2.5 mM 2,4-diHB, as well as COQ9R239X mice with 100-200mg/kg bw*day of oral 2,4-diHB [3,4]. At those doses, CoQ10 levels were significantly increased in COQ9R244X fibroblasts. Likewise, CoQ9 levels were slightly increased in kidneys and skeletal muscle homogenates. In isolated mitochondria, CoQ9 levels were also increased in kidney and skeletal muscle resulting in an increase of complex I&III activities. However, the levels of CoQ9 and the CI&III activity were similar in brain of untreated and treated COQ9R239X mice and, as a consequence, the histopathological characteristics of COQ9R239X mice were unaffected after the treatment. These results point out that it is possible to bypass a defect in CoQ biosynthesis in vitro and in vivo. However, the results in brain suggest that this tissue has a specific regulation of CoQ biosynthesis or that a higher dose of 2,4-diHB is required to increase CoQ biosynthesis in brain.
Labels: MiParea: mtDNA;mt-genetics, mt-Medicine, Pharmacology;toxicology Pathology: Other Stress:Mitochondrial disease Organism: Mouse Tissue;cell: Skeletal muscle, Nervous system, Kidney, Fibroblast Preparation: Homogenate, Isolated mitochondria
Event: A3, Oral MiP2015
1-Dept Fisiología, Facultad Medicina, Univ Granada, Spain; 2-Centro Investigación Bioméd, Inst Biotecnología, Parque Tecnológico Ciencias de la Salud, Granada, Spain; 3-Dept Neurology, Columbia Univ Med Center, New York, NY, USA. - firstname.lastname@example.org
References and acknowledgements
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