β‐ RA reduces DMQ /CoQ ratio and rescues the encephalopathic phenotype in Coq9 ^R239X mice

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 Coq9 R239X 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 (DMQ 9) 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.

Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells LackingCOQ6

“…Bypass therapy is a promising alternative to conventional CoQ supplementation for patients with primary CoQ deficiency and has been successfully tested in mouse models of COQ7 and COQ9 defects [25, 26] and in cells of patients with COQ7 mutations [27, 28]. In particular, mice with a conditional ablation of the Coq7 gene (which encodes the C6-hydroxylase catalyzing the penultimate step of CoQ biosynthesis) at 2 months of age developed severe, multiorgan CoQ deficiency, which lead to death after 9 months.…”

Metabolic Targets of Coenzyme Q10 in Mitochondria

“…In Pdss2 kd/kd mice, CoQ 10 supplementation does not rescue the CoQ-dependent complexes activities in kidneys, although therapeutic benefits were reported, presumably due to other CoQ 10 functions [47,49]. In Coq9 R239X mice, ubiquinol-10 (CoQ 10 H 2 ), but not ubiquinone-10 (CoQ 10 ), is able to partially increase CI + III activity in the brain due to its superior absorption, bioavailability and mitochondrial uptake [50], leading to an increase in survival [51]. Since Coq9 R239X mice accumulates DMQ, the reduction in the levels of DMQ achieved by the treatment with beta-resorcylic acid (β-RA) is able to increase the bioenergetics and obtain therapeutic outcomes that are superior to those obtained under CoQ 10 H 2 supplementation [51].…”

Mitochondrial disorders and drugs: what every physician should know

“…Simple coenzyme Q10 derivatives may act to enhance biosynthesis of coenzyme Q10 or may bypass certain deficient steps in the coenzyme Q10 biosynthetic pathway 36. For instance, β-resorcylic acid was reported to be more effective than coenzyme Q10 in a mouse model of coenzyme Q10 deficiency with an encephalopathic phenotype 37. β-resorcylic acid is an analog of the coenzyme Q10 precursor 4-hydroxybenzoic acid 37.…”

“…For instance, β-resorcylic acid was reported to be more effective than coenzyme Q10 in a mouse model of coenzyme Q10 deficiency with an encephalopathic phenotype 37. β-resorcylic acid is an analog of the coenzyme Q10 precursor 4-hydroxybenzoic acid 37. Further studies are needed to evaluate if its use could be considered in human coenzyme Q10 deficiencies.…”