Reference

EMBO Molecular Medicine (2019) 11, e9466 Journal Cover Embo

Authors

Agustín Hidalgo‐Gutiérrez, Eliana Barriocanal‐Casado, Mohammed Bakkali, M Elena Díaz‐Casado, Laura Sánchez‐Maldonado, Miguel Romero, Ramy K Sayed, Cornelia Prehn, Germaine Escames, Juan Duarte, Darío Acuña‐Castroviejo,Luis C López.

Abstract

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 Coq9R239X mouse model with fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of β‐resorcylic acid (β‐RA), a structural analog of the CoQ precursor 4‐hydroxybenzoic acid and the anti‐inflammatory salicylic acid. β‐RA noticeably rescued the phenotypic, morphological, and histopathological signs of the encephalopathy, leading to a significant increase in the survival. Those effects were due to the decrease of the levels of demethoxyubiquinone‐9 (DMQ9) and the increase of mitochondrial bioenergetics in peripheral tissues. However, neither CoQ biosynthesis nor mitochondrial function changed in the brain after the therapy, suggesting that some endocrine interactions may induce the reduction of the astrogliosis, spongiosis, and the secondary down‐regulation of astrocytes‐related neuroinflammatory genes. Because the therapeutic outcomes of β‐RA administration were superior to those after CoQ10 supplementation, its use in the clinic should be considered in CoQ deficiencies.

Description

La deficiencia en CoQ es un tipo de enfermedad rara de origen mitocondrial. Esta enfermedad cursa con diferentes fenotipos apareciendo los síntomas principalmente a edad muy temprana. Una de las variantes más graves es la encefalopática, para la que no existe tratamiento efectivo actualmente. En este artículo describimos una terapia basada en el uso de un análago del precursor principal de la biosíntesis de la CoQ, obteniendo unos resultados terapéuticos extraordinarios en ratones afectados por la variante encefalopática, gracias al ahondamiento en la bioquímica de la ruta biosintética de la CoQ, llegando la curva de supervivencia a niveles cercanos a los wild type.

 

 

Foto grupal. Agustín Hidalgo

 

REFERENCIA DEL GRUPO INVESTIGADOR

El artículo ha sido desarrollado en el MitoLab dirigido por el profesor Luis Carlos López García encuadrado dentro del grupo CTS-101 de la UGR. El objetivo del MitoLab es comprender mejor la biología de la mitocondria, así como utilizar este entendimiento para la búsqueda de tratamientos efectivos frente a las distintas patologías mitocondriales. El artículo ha sido desarrollado principalmente por Agustín Hidalgo, biólogo y becario FPU de 2º año; junto con la ayuda de Eliana Barriocanal, biotecnóloga y contratada por la Junta de Andalucía. http://wpd.ugr.es/~luisca/research/

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