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.

Keywords::

• ATP synthase
• reactive oxygen species
• COQ genes
• PGC-1alpha
• N-acetylcysteine

Declaration of interest

This study was supported by the following grants to H.C. Yen from Ministry of Science and Technology (formerly known as National Science Council), Taiwan: NSC100-2320-B-182-014, NSC101-2320-B182-028, and NSC102-2320-B-182-026-MY3. The authors report no conflict of interests. The grant funder plays no role in the study design, data acquisition, or manuscript preparation. The authors alone are responsible for the content and writing of the paper.