Publication:
The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency.

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Date

2022-07-10

Authors

Gonzalez-Garcia, Pilar
Diaz-Casado, Maria Elena
Hidalgo-Gutierrez, Agustin
Jimenez-Sanchez, Laura
Bakkali, Mohammed
Barriocanal-Casado, Eliana
Escames, Germaine
Chiozzi, Riccardo Zenezini
Völlmy, Franziska
Zaal, Esther A

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Elsevier BV
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Abstract

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.

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MeSH Terms

Mice
Animals
Coenzyme Q10 Deficiency
Ubiquinone
Vanillic Acid
Proteome
Neuroinflammatory Diseases
Neurodegenerative Diseases
Gliosis
Mitochondrial Diseases
Metabolic Diseases
Brain
Phenotype
Kidney
Biomarkers

DeCS Terms

Animales
Biomarcadores
Coenzimas
Encéfalo
Enfermedades metabólicas
Enfermedades mitocondriales
Enfermedades neurodegenerativas
Enfermedades neuroinflamatorias
Fenotipo
Gliosis
Proteoma
Ratones

CIE Terms

Keywords

Coenzyme Q, Mitochondrial disease, Omics, Phenolic compound, Therapy

Citation

González-García P, Díaz-Casado ME, Hidalgo-Gutiérrez A, Jiménez-Sánchez L, Bakkali M, Barriocanal-Casado E, et al. The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency. Redox Biol. 2022 Sep;55:102403.