MitoQ regulates autophagy by inducing a pseudo-mitochondrial membrane potential

• Published in: Autophagy Vol. 13; no. 4; pp. 730 - 738
• Main Authors: Sun, Chao, Liu, Xiongxiong, Di, Cuixia, Wang, Zhenhua, Mi, Xiangquan, Liu, Yang, Zhao, Qiuyue, Mao, Aihong, Chen, Weiqiang, Gan, Lu, Zhang, Hong
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 03.04.2017
• Subjects: Adenylate Kinase - metabolism; autophagy; Autophagy - drug effects; Basic Research Paper; Cell Proliferation - drug effects; Energy Metabolism; Hep G2 Cells; Humans; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; MitoQ; Organophosphorus Compounds - pharmacology; proton displacement; pseudo-MMP; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; autophagy; MitoQ; pseudo-MMP; energy metabolism; proton displacement
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2017.1280219

During the process of oxidative phosphorylation, protons are pumped into the mitochondrial intermembrane space to establish a mitochondrial membrane potential (MMP). The electrochemical gradient generated allows protons to return to the matrix through the ATP synthase complex and generates ATP in the process. MitoQ is a lipophilic cationic drug that is adsorbed to the inner mitochondrial membrane; however, the cationic moiety of MitoQ remains in the intermembrane space. We found that the positive charges in MitoQ inhibited the activity of respiratory chain complexes I, III, and IV, reduced proton production, and decreased oxygen consumption. Therefore, a pseudo-MMP (PMMP) was formed via maintenance of exogenous positive charges. Proton backflow was severely impaired, leading to a decrease in ATP production and an increase in AMP production. Excess AMP activates AMP kinase, which inhibits the MTOR (mechanistic target of rapamycin) pathway and induces macroautophagy/autophagy. Therefore, we conclude that MitoQ increases PMMP via proton displacement with exogenous positive charges. In addition, PMMP triggered autophagy in hepatocellular carcinoma HepG2 cells via modification of mitochondrial bioenergetics pathways.