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.