How the mitochondrion was shaped by radical differences in substrates: what carnitine shuttles and uncoupling tell us about mitochondrial evolution in response to ROS.

As free-living organisms, alpha-proteobacteria produce reactive oxygen species (ROS) that diffuse into the surroundings; once constrained inside the archaeal ancestor of eukaryotes, however, ROS production presented evolutionary pressures - especially because the alpha-proteobacterial symbiont made more ROS, from a variety of substrates. I previously proposed that ratios of electrons coming from FADH2 and NADH (F/N ratios) correlate with ROS production levels during respiration, glucose breakdown having a much lower F/N ratio than longer fatty acid (FA) breakdown. Evidently, higher endogenous ROS formation did not hinder eukaryotic evolution, so how were its disadvantages mitigated? I propose that the resulting selection pressures favoured the evolution of a variety of eukaryotic 'innovations': peroxisomes for FA breakdown, carnitine shuttles, the linkage of beta-oxidation to antioxidant properties, uncoupling proteins (UCPs) and using mitochondrial uncoupling during beta-oxidation to reduce ROS. Recently observed relationships between peroxisomes and mitochondria further support the model.