title: MitoQ regulates autophagy by inducing a pseudo-mitochondrial membrane potential.
abstract: 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.
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.
authors.forename: Xiongxiong
authors.initials: X
authors.lastname: Liu
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Di
authors.affiliation: d College of Life Sciences , Yantai University , Yantai , China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: e College of Life Sciences , Lanzhou University , Lanzhou , China.
authors.forename: Xiangquan
authors.initials: X
authors.lastname: Mi
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.
authors.forename: Qiuyue
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.
authors.forename: Aihong
authors.initials: A
authors.lastname: Mao
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Chen
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.affiliation: a Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.|b Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences , Lanzhou , China.|c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province , Lanzhou , China.|f Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions , Suzhou , China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism; D056945:Hep G2 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D009943:Organophosphorus Compounds; D014451:Ubiquinone; C429014:mitoquinone; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase
keywords: MitoQ; autophagy; energy metabolism; proton displacement; pseudo-MMP