Can All Major ROS Forming Sites of the Respiratory Chain Be Activated By High FADH₂/NADH Ratios? Ancient evolutionary constraints determine mitochondrial ROS formation

Aspects of peroxisome evolution, uncoupling, carnitine shuttles, supercomplex formation, and missing neuronal fatty acid oxidation (FAO) are linked to reactive oxygen species (ROS) formation in respiratory chains. Oxidation of substrates with high FADH₂/NADH (F/N) ratios (e.g., FAs) initiate ROS formation in Complex I due to insufficient availability of its electron acceptor (Q) and reverse electron transport from QH₂, e.g., during FAO or glycerol-3-phosphate shuttle use. Here it is proposed that the Q-cycle of Complex III contributes to enhanced ROS formation going from low F/N ratio substrates (glucose) to high F/N substrates. This contribution is twofold: 1) Complex III uses Q as substrate, thus also competing with Complex I; 2) Complex III itself will produce more ROS under these conditions. I link this scenario to the universally observed Complex III dimerization. The Q-cycle of Complex III thus again illustrates the tension between efficient ATP generation and endogenous ROS formation. This model can explain recent findings concerning succinate and ROS-induced uncoupling.