MitoQ regulates autophagy by inducing a pseudo-mitochondrial membrane potential

Area of Science:

• Mitochondrial bioenergetics
• Cellular signaling
• Drug-induced cellular effects

Background:

• Oxidative phosphorylation generates mitochondrial membrane potential (MMP) for ATP synthesis.
• MitoQ is a lipophilic cation that localizes to mitochondria.
• The cationic nature of MitoQ influences mitochondrial function.

Purpose of the Study:

• To investigate the effects of MitoQ on mitochondrial membrane potential and cellular bioenergetics.
• To elucidate the mechanism by which MitoQ impacts ATP production and induces autophagy.
• To determine if MitoQ triggers autophagy in hepatocellular carcinoma cells.

Main Methods:

• Assessing the impact of MitoQ on respiratory chain complex activity.
• Measuring proton production and oxygen consumption in the presence of MitoQ.
• Evaluating ATP and AMP production.
• Investigating the activation of AMP kinase and the mechanistic target of rapamycin (MTOR) pathway.
• Inducing and observing autophagy in HepG2 cells.

Main Results:

• MitoQ inhibited respiratory chain complexes I, III, and IV, reducing proton production and oxygen consumption.
• MitoQ induced a pseudo-MMP (PMMP) by displacing protons with exogenous positive charges.
• Proton backflow was impaired, decreasing ATP production and increasing AMP production.
• Increased AMP activated AMP kinase, inhibiting the MTOR pathway and inducing autophagy.
• PMMP triggered autophagy in HepG2 cells through alterations in mitochondrial bioenergetics.

Conclusions:

• MitoQ increases PMMP by displacing protons with exogenous positive charges.
• PMMP impairs mitochondrial bioenergetics, leading to decreased ATP production and increased autophagy.
• MitoQ-induced PMMP triggers autophagy in hepatocellular carcinoma cells, suggesting a potential therapeutic mechanism.