4-Hydroxybenzoic acid rescues multisystemic disease and perinatal lethality in a mouse model of mitochondrial disease Corral Sarasa, Julia Martínez Gálvez, Juan Manuel González García, Pilar Wendling, Olivia Jiménez Sánchez, Laura López Herrador, Sergio Quinzii, Catarina M. Díaz Casado, María Elena López García, Luis Carlos Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency. 2024-07-29T10:13:48Z 2024-07-29T10:13:48Z 2024-05-01 journal article Corral-Sarasa et al. 4-Hydroxybenzoic acid rescues multisystemic disease and perinatal lethality in a mouse model of mitochondrial disease 2024, Cell Reports 43, 114148 [10.1016/j.celrep.2024.114148] https://hdl.handle.net/10481/93548 10.1016/j.celrep.2024.114148 eng http://creativecommons.org/licenses/by-nc/4.0/ open access Atribución-NoComercial 4.0 Internacional Elsevier