The clinical phenotypes of human CoQ10-deficiency caused by COQ2 mutations range from fatal neonatal disease to adult-onset multisystem atrophy. So far, treatment options for these diseases are unsatisfactory. Here, we demonstrate that supplementation of 4-hydroxybenzoic acid (4-HBA) fully restores endogenous CoQ10-biosynthesis in COQ2-deficient cell lines. This was accompanied by increased protein expression of CoQ10-biosynthesis-enzymes as well as a rescue of cell viability during stress conditions. In silico analysis suggested a ligand transportation path for 4-HBA through the COQ2 protein towards the mitochondrial matrix side. This process is apparently hindered by disease-causing mutations, which can be overcome by increasing 4-HBA concentrations.