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.

Co-SLD suppressed the growth of oral squamous cell carcinoma via disrupting mitochondrial function

“…Cellular ATP, ADP and AMP after Co-SLD treatments were determined by HPLC analysis as previously described [48]. The HPLC conditions were as follows: a reverse phase C18 column (Agilent Technologies, Santa Clara, CA, USA); a mobile phase containing 35 mM NaH 2 PO 4 , 6 mM tetrabutylammonium; mobile phase: acetonitrile gradient 95:5 to 75:25.…”

The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue

“…Moreover, MitoQ has also been found to induce autophagy in liver cells (Sun et al. ). Thus, there is a pressing need to better understand the detailed effects of MitoQ on mitochondrial function in kidney tissue.…”

“…For example, a recent study has reported that MitoQ can actually increase ROS production in some cancer cells, and this is associated with a decrease in Dw m and mitochondrial DNA (mtDNA) copy number (Pokrzywinski et al 2016). Moreover, MitoQ has also been found to induce autophagy in liver cells (Sun et al 2017). Thus, there is a pressing need to better understand the detailed effects of MitoQ on mitochondrial function in kidney tissue.…”

Mitochondria, the NLRP3 Inflammasome, and Sirtuins in Type 2 Diabetes: New Therapeutic TargetsReviewing Editors:Markus Bachschmid, Dylan Burger, Vittorio Calabrese, Amadou Camara, Lukas Kubala, Giuseppe Poli, and Chandan K. Sen

“…Other studies have reported that MitoQ is beneficial in different pathologies, including sepsis and cardiometabolic diseases (193). Since MitoQ has positive charges and is located at the IMM, it can generate a pseudo-DCm via proton displacement with exogenous positive charges, which eventually promotes autophagy in HepG2 cells (309).…”