Figure 7. Schematic representation of NQO1-dependent cytosolic-mitochondrial electron shuttling.

(A) During oxidative phosphorylation under normal conditions, CoQ₁₀ transports electrons from complex I (CI) to complex III (CIII) and cytochrome c, reduced by complex III, transfers them to complex IV. As a consequence of this electron propagation, all three complexes translocate protons (H⁺) across the mitochondrial membrane, thus generating a proton gradient. ATP synthase utilizes the energy stored in this electro-chemical gradient to generate ATP. (B) Upon rotenone-induced (Rot) inhibition of complex I, ATP levels decrease dramatically (see also results of Fig. 3). (C) Some short-chain quinones (Q) such as idebenone or CoQ₁ can bypass complex I inhibition via a cytosolic-mitochondrial shuttling of electrons. Upon reduction by cytosolic NQO1 (QH₂), these quinones can feed electrons into the mitochondrial respiratory chain in a complex III-dependent manner, thereby restoring ATP production.