The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency
Metadatos
Mostrar el registro completo del ítemAutor
González García, Pilar; Díaz Casado, María Elena; Hidalgo Gutiérrez, Agustín; Jiménez Sánchez, Laura; Bakkali, Mohammed; Barriocanal Casado, Eliana; Escames Rosa, Germaine; López García, Luis CarlosEditorial
Elsevier
Materia
Coenzyme Q Mitochondrial disease Therapy Omics Phenolic compound
Fecha
2022-07-15Referencia bibliográfica
Pilar González-García... [et al.]. The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency, Redox Biology, Volume 55, 2022, 102403, ISSN 2213-2317, [https://doi.org/10.1016/j.redox.2022.102403]
Patrocinador
MCIN/AEI, Spain; European Commission RTI2018093503-B-100; Muscular Dystrophy Association MDA-602322; Junta de Andalucia P20_00134 PEER-00832020; EPIC-XS - Horizon 2020 programme of the European Union 823839; "Plan Propio de Investigacion" from the University of Granada Junta de AndaluciaResumen
Defects in Coenzyme Q (CoQ) metabolism have been associated with primary mitochondrial disorders, neurodegenerative
diseases and metabolic conditions. The consequences of CoQ deficiency have not been fully
addressed, and effective treatment remains challenging. Here, we use mice with primary CoQ deficiency
(Coq9R239X), and we demonstrate that CoQ deficiency profoundly alters the Q-junction, leading to extensive
changes in the mitochondrial proteome and metabolism in the kidneys and, to a lesser extent, in the brain. CoQ
deficiency also induces reactive gliosis, which mediates a neuroinflammatory response, both of which lead to an
encephalopathic phenotype. Importantly, treatment with either vanillic acid (VA) or β-resorcylic acid (β-RA), two
analogs of the natural precursor for CoQ biosynthesis, partially restores CoQ metabolism, particularly in the
kidneys, and induces profound normalization of the mitochondrial proteome and metabolism, ultimately leading
to reductions in gliosis, neuroinflammation and spongiosis and, consequently, reversing the phenotype.
Together, these results provide key mechanistic insights into defects in CoQ metabolism and identify potential
disease biomarkers. Furthermore, our findings clearly indicate that the use of analogs of the CoQ biosynthetic
precursor is a promising alternative therapy for primary CoQ deficiency and has potential for use in the treatment
of more common neurodegenerative and metabolic diseases that are associated with secondary CoQ deficiency.