Figure 7.

Proposed mechanism of MPP⁺ toxicity at the IMM level. MPP⁺ promotes the impairment of complex I activity. Electrons are then addressed towards other substrates, increasing ROS production (electron leaking). The reduced activity of complex I affects MDH activity as well as the accumulation of the Krebs cycle intermediates and complex II inhibitor oxaloacetate. In this perspective, the activity of complex II raises since it is less subjected to oxaloacetate inhibition. MPP⁺ also induces UCPs gene expression. The increased activity of UCP proteins dissipates partially the proton gradients (proton leaking), a mechanism called “mild uncoupling” and aimed to counteract ROS damage. Original figure (created with https://smart.servier.com tools).