Figure 1.

Proposed mechanism of increased ROS production by inhibited complex II following PTP opening. Left panel, under physiological conditions succinate (S) oxidation by complex II (succinate dehydrogenase composed of four subunits SDHA–D) results in flavin site reduction (FADH₂ generation) and further tunneling of electrons via Fe-S clusters to ubiquinone (Q) in the Q-binding site that generates ubiquinol (QH2) by two sequential single electron transfers, requiring also two protons. QH2 is further oxidized by complex III. No ROS are generated under those conditions because the flavin site is rapidly oxidized if there is no downstream inhibition, and dicarboxylates such as succinate and fumarate (F) shield access of O₂ to their binding site. Right panel, when electron transport is inhibited at the level of Q reduction by AA5 or further downstream, FADH₂ accumulates. After PTP opening in the inner membrane, matrix succinate/fumarate levels decrease, giving O₂ access to reduced flavin site to generate ROS.