Figure 8
A proposed model of cell death initiation at CII explaining the regulation of ROS production from reduced FAD group in intact cells. (a) High-affinity Qp site inhibitors, such as Atpenin A5, will immediately block most of the available Qp sites in a cell and rapidly upregulate intracellular succinate. CII will be inhibited and FAD reduced, but no ROS will be produced, because succinate in the dicarboxylate site will block oxygen access. (b) Medium affinity inhibition such as with MitoVES or TTFA will not immediately block all the available Qp sites, and some free CII will be left to keep succinate levels from rising rapidly. Because of the free dicarboxylate site, the reduced FAD in Qp-inhibited CII molecules will be able to produce cell death-inducing ROS. (c) Mutations in the Qp site that do not affect CII activity will lower the ability of an inhibitor such as MitoVES to displace ubiquinone, and despite low intracellular succinate FAD will not be reduced and therefore unable to produce ROS. (d) Qp site mutations that affect CII activity will upregulate succinate, blocking dicarboxylate site and preventing ROS generation from FAD. Additional Qp site inhibition will not generate ROS under these conditions
