González-García Pilar, Jiménez-Sánchez Laura, Corral-Sarasa Julia, López-Herrador Sergio, Torres-Rusillo Sara, Díaz-Casado María Elena, López Luis C
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
Commun Med (Lond). 2025 Jul 10;5(1):286. doi: 10.1038/s43856-025-01000-8.
Primary coenzyme Q (CoQ) deficiency is a severe mitochondrial disorder characterized by diverse clinical manifestations due to multiple pathomechanisms. Although CoQ supplementation remains the standard treatment, its therapeutic efficacy is limited by poor bioavailability and restricted tissue distribution, especially to the central nervous system.
In this study, we investigated the therapeutic potential of combining CoQ with vanillic acid (VA), a structural analog of 4-hydroxybenzoic acid, in both murine and human models of primary CoQ deficiency, through phenotypic, biochemical, and molecular analyses.
In Coq9 mice, we demonstrate that co-administration of CoQ and VA significantly extends lifespan and improves motor function beyond the effects observed with either compound alone. Mechanistically, this enhanced therapeutic efficacy results from the complementary actions of both compounds, i.e., CoQ increases quinone pools in peripheral tissues and modulates one-carbon metabolism, particularly in the liver, while VA reduces DMQ accumulation in the kidney and liver and exhibits potent anti-neuroinflammatory properties, leading to a reduction in gliosis. The co-treatment shows remarkable tissue-specific responses, with the liver displaying the most pronounced metabolic adaptations. In this tissue, the combined therapy restores the expression of genes involved in sulfide oxidation and one-carbon metabolism pathways. We further validate these findings in human COQ7-deficient fibroblasts, where the co-treatment normalizes key metabolic pathways more effectively than individual treatments.
Our findings demonstrate that combining CoQ with VA effectively addresses multiple pathogenic mechanisms in CoQ deficiency, resulting in enhanced therapeutic outcomes. This therapeutic strategy could represent a more effective and feasible treatment approach for mitochondrial disorders, particularly those involving CoQ deficiency and neurological manifestations.
原发性辅酶Q（CoQ）缺乏症是一种严重的线粒体疾病，由于多种发病机制而具有多种临床表现。尽管补充CoQ仍然是标准治疗方法，但其治疗效果受到生物利用度差和组织分布受限的限制，尤其是在中枢神经系统中。
在本研究中，我们通过表型、生化和分子分析，研究了在原发性CoQ缺乏的小鼠和人类模型中，将CoQ与香草酸（VA，4-羟基苯甲酸的结构类似物）联合使用的治疗潜力。
在Coq9小鼠中，我们证明CoQ和VA联合给药显著延长了寿命，并改善了运动功能，其效果超过单独使用任何一种化合物所观察到的效果。从机制上讲，这种增强的治疗效果源于两种化合物的互补作用，即CoQ增加外周组织中的醌池并调节一碳代谢，特别是在肝脏中，而VA减少肾脏和肝脏中DMQ的积累，并表现出强大的抗神经炎症特性，导致胶质细胞增生减少。联合治疗显示出显著的组织特异性反应，肝脏表现出最明显的代谢适应性。在该组织中，联合治疗恢复了参与硫化物氧化和一碳代谢途径的基因表达。我们在人类COQ7缺陷成纤维细胞中进一步验证了这些发现，其中联合治疗比单独治疗更有效地使关键代谢途径正常化。
我们的研究结果表明，将CoQ与VA联合使用可有效解决CoQ缺乏症中的多种致病机制，从而提高治疗效果。这种治疗策略可能代表一种更有效、可行的线粒体疾病治疗方法，特别是那些涉及CoQ缺乏和神经学表现的疾病。
