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Hidalgo-Gutierrez 2015 Abstract MiP2015

From Bioblast
Strategies to enhance the endogenous biosynthesis of Coenzyme Q.


Hidalgo-Gutierrez A, Luna-Sanchez M, Barriocanal-Casado E, Quinzii CM, Lopez LC (2015)

Event: MiP2015

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 [1]. 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 [1]. In those cases, the stimulation of endogenous CoQ10 biosynthesis could be an alternative and effective therapeutic option [2]. 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 Fisiolog铆a, Facultad Medicina, Univ Granada, Spain; 2-Centro Investigaci贸n Biom茅d, Inst Biotecnolog铆a, Parque Tecnol贸gico Ciencias de la Salud, Granada, Spain; 3-Dept Neurology, Columbia Univ Med Center, New York, NY, USA. - [email protected]

References and acknowledgements

  1. Emmanuele V, L贸pez LC, Berardo A, Naini A, Tadesse S, Wen B, D鈥橝gostino E, Salomon M, DiMauro S, Quinzii CM, Hirano M (2012) Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol 69:978-83.
  2. Luna-Sanchez M, D铆az-Casado E, Barca E, Tejada MA, Montilla-Garcia A, Cobos EJ, Escames G, Acu帽a-Castroviejo D, Quinzii CM, L贸pez LC (2015) The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences inthe Coq9 gene. EMBO Molecular Medicine 7:670-87.
  3. Garc铆a-Corzo L, Luna-S谩nchez M, Doerrier C, Ortiz F, Escames G, Acu帽a-Castroviejo D, L贸pez LC (2014) Ubiquinol-10 amelioratesmitochondrial encephalopathy associated with CoQ deficiency. Biochimica et Biophysica Acta 1842:893鈥901.
  4. Duncan AJ, Bitner-Glindzicz M, Meunier B, Costello H, Hargreaves LP, L贸pez LC, Hirano M, Quinzii CM, Sadowski MI, Hardy J, Singleton A, Clayton PT, Rahman S (2009) A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. AM J Hum Genet 84:558鈥66.