Luna-Sánchez 2014 Abstract SECF
|Mitochondrial encephalopathy due to coenzyme q deficiency: pathogenesis and treatment.|
Coenzyme Q10 (CoQ10) deficiency (OMIM 607426) causes a mitochondrial syndrome with a nonunderstandable variability in the clinical presentations. Moreover, patients with CoQ10 deficiency show inconsistent responses to oral ubiquinone-10 supplementation, with the highest percentage of unsuccessful results in patients with neurological symptoms (encephalopathy, cerebellar ataxia or multisystemic disease). To better understand the pathophysiology of CoQ deficiency syndrome and evaluate experimental therapies, we have generated a unique mouse model (Coq9X/X) of CoQ deficiency. Our characterization of Coq9X/X mice has demonstrated that: (i) the presence of a dysfunctional Coq9 protein and/or the deficit in CoQ in the brain causes an increase in free complex III, leading to a decrease in mitochondrial respiration and ATP synthesis, (ii) mitochondrial dysfunction in the brain induces oxidative damage and a caspase-independent apoptotic cell death and (iii) the encephalomyopathic form of CoQ deficiency is progressive and takes place with neuronal death, severe reactive astrogliosis and spongiform degeneration. Additionally, we have evaluated oral supplementation with water-soluble formulations of reduced (ubiquinol-10) and oxidized (ubiquinone-10) forms of CoQ10. The treatment evaluation shows that CoQ10 was increased in all tissues after supplementation with ubiquinone-10 or ubiquinol-10, with the tissue levels of CoQ10 with ubiquinol-10 being higher than with ubiquinone-10. Moreover, only ubiquinol-10 was able to increase the levels of CoQ10 in mitochondria from cerebrum of Coq9X/X mice. Consequently, ubiquinol-10 was more efficient than ubiquinone-10 in increasing CoQdependent respiratory chain complex activities, and reducing the vacuolization, astrogliosis and oxidative damage in diencephalon, septum-striatum and, to a lesser extent, in brainstem. As a result, ubiquinol-10 treatment was able to increase the animal body weight and the survival of Coq9X/X mice. Taken together, our results suggest that the bioenergetics impairment and the increased oxidative stress seem to be key components in the understanding of the encephalopatyc form of CoQ deficiency. Furthermore, water-soluble formulations of ubiquinol-10 may improve the efficacy of CoQ10 therapy in primary and secondary CoQ10 deficiencies, other mitochondrial diseases and mitochondrial-related diseases.
• Keywords: mitochondria, astrogliosis, therapy
• O2k-Network Lab: ES Granada Acuna-Castroviejo D
Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology
Stress:Mitochondrial disease Organism: Mouse
Preparation: Isolated mitochondria Enzyme: Supercomplex Regulation: ATP production
HRR: Oxygraph-2k Event: Oral
1-Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avda. Del Conocimiento s/n, 18100 Armilla, Granada, Spain. 2-Departamento de Fisiología, Facultad de Medicina,Universidad de Granada, Avenida de Madrid 11, 18012 Granada, Spain.