Defining the mechanism of action of S1QELs, specific suppressors of superoxide production in the quinone-reaction site in mitochondrial complex I

I]AzQ) to the 49-kDa subunit. Moreover, a photoaffinity labeling experiment with photoreactive S1QEL derivatives indicated that they bind to a segment in the ND1 subunit that is not considered to make up the binding pocket for quinone or inhibitors. These results indicate that unlike known quinone-site inhibitors, S1QELs do not occupy the quinone- or inhibitor-binding pocket; rather, they may indirectly modulate the quinone-redox reactions by inducing structural changes of the pocket through binding to ND1. We conclude that this indirect effect may be a prerequisite for S1QELs' direction-dependent modulation of electron transfer. This, in turn, may be responsible for the suppression of superoxide production during reverse electron transfer without significantly interfering with forward electron transfer.