FIG. 4.

Proposed modes of action of metformin on the main sources of ROS production. (A) Metformin reduces mROS generated by electrons leaked from the ETC during reverse electron transfer by inhibiting the ETC complex I and mGPDH. (B) Mitochondrial permeability transition pore formation is triggered in part by mROS, which generates a second wave of mROS through ROS-induced ROS release. Whether metformin has any effect on this process is unknown. (C) NOX in the plasma membrane generates cytoplasmic ROS. Metformin has not been reported to interfere with this process. NOX, NADPH-oxidase; ROS, reactive oxygen species; mROS, mitochondrial ROS. Color images are available online.