title: Effects of inhibiting CoQ10 biosynthesis with 4-nitrobenzoate in human fibroblasts.
abstract: Coenzyme Q(10) (CoQ(10)) is a potent lipophilic antioxidant in cell membranes and a carrier of electrons in the mitochondrial respiratory chain. We previously characterized the effects of varying severities of CoQ(10) deficiency on ROS production and mitochondrial bioenergetics in cells harboring genetic defects of CoQ(10) biosynthesis. We observed a unimodal distribution of ROS production with CoQ(10) deficiency: cells with <20% of CoQ(10) and 50-70% of CoQ(10) did not generate excess ROS while cells with 30-45% of CoQ(10) showed increased ROS production and lipid peroxidation. Because our previous studies were limited to a small number of mutant cell lines with heterogeneous molecular defects, here, we treated 5 control and 2 mildly CoQ(10) deficient fibroblasts with varying doses of 4-nitrobenzoate (4-NB), an analog of 4-hydroxybenzoate (4-HB) and inhibitor of 4-para-hydroxybenzoate:polyprenyl transferase (COQ2) to induce a range of CoQ(10) deficiencies. Our results support the concept that the degree of CoQ(10) deficiency in cells dictates the extent of ATP synthesis defects and ROS production and that 40-50% residual CoQ(10) produces maximal oxidative stress and cell death.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Catarina M
authors.initials: CM
authors.lastname: Quinzii
authors.forename: Saba
authors.initials: S
authors.lastname: Tadesse
authors.forename: Ali
authors.initials: A
authors.lastname: Naini
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D016923:Cell Death; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D009579:Nitrobenzoates / Q000494:pharmacology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D009579:Nitrobenzoates; D017382:Reactive Oxygen Species; D014451:Ubiquinone; D000255:Adenosine Triphosphate; C024989:coenzyme Q10; C008629:4-nitrobenzoic acid