Fig. 4.

Summary of simulations on the effect of complex III and IV deficiency on metabolism.

As maximum flux through either complex III or IV was reduced in the simulations (grey), there was a dramatic decrease in ATP production. Inhibiting complexes III and IV effectively blocks the respiratory chain. However, simulations predicted complex I continued pumping protons (and so supported the F-ATPase in producing ATP) if complex II ran in reverse and reduced fumarate to succinate—the NADH-fumarate reductase system (NFRS). Three pathways, which used a partial reversal of the TCA cycle, supplied the required fumarate for the NFRS: the purine nucleotide cycle, aspartate transaminase, and reductive carboxylation.