title: Suppression of coenzyme Q₁₀ levels and the induction of multiple PDSS and COQ genes in human cells following oligomycin treatment.
abstract: Endogenous coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant and essential for the electron transport chain. We previously demonstrated that hydrogen peroxide enhanced CoQ10 levels, whereas disruption of mitochondrial membrane potential by a chemical uncoupler suppressed CoQ10 levels, in human 143B cells. In this study, we investigated how CoQ10 levels and expression of two PDSS and eight COQ genes were affected by oligomycin, which inhibited ATP synthesis at Complex V without uncoupling the mitochondria. We confirmed that oligomycin increased the production of reactive oxygen species (ROS) and decreased mitochondria-dependent ATP production in 143B cells. We also demonstrated that CoQ10 levels were decreased by oligomycin after 42 or 48 h of treatment, but not at earlier time points. Expression of PDSS2 and COQ2-COQ9 were up-regulated after 18-hour oligomycin treatment, and the expression of PPARGC1A (PGC1-1α) elevated concurrently. Knockdown of PPARGC1A down-regulated the basal mRNA levels of PDSS2 and five COQ genes and suppressed the induction of COQ8 and COQ9 genes by oligomycin, but did not affect CoQ10 levels under these conditions. N-acetylcysteine suppressed the augmentation of ROS levels and the enhanced expression of COQ2, COQ4, COQ7, and COQ9 induced by oligomycin, but did not modulate the changes in CoQ10 levels. These results suggested that the condition of mitochondrial dysfunction induced by oligomycin decreased CoQ10 levels independent of oxidative stress. Up-regulation of PDSS2 and several COQ genes by oligomycin might be regulated by multiple mechanisms, including the signaling pathways mediated by PGC-1α and ROS, but it would not restore CoQ10 levels.
authors.affiliation: Department and Graduate Institute of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University , Taoyuan , Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Yen
authors.forename: C-C
authors.initials: CC
authors.lastname: Liu
authors.forename: C-C
authors.initials: CC
authors.lastname: Kan
authors.forename: C-S
authors.initials: CS
authors.lastname: Chen
authors.forename: H-R
authors.initials: HR
authors.lastname: Wei
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D009840:Oligomycins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D014451:Ubiquinone; D000255:Adenosine Triphosphate; D019883:Alkyl and Aryl Transferases; C540142:prenyl diphosphate synthase, subunit 2, human; C024989:coenzyme Q10
keywords: ATP synthase; COQ genes; N-acetylcysteine; PGC-1alpha; reactive oxygen species