Oxygen radicals shaping evolution: Why fatty acid catabolism leads to peroxisomes while neurons do without it

Abstract

Oxygen radical formation in mitochondria is a highly important, but incompletely understood, attribute of eukaryotic cells. I propose a kinetic model in which the ratio between electrons entering the respiratory chain via FADH₂ or NADH is a major determinant in radical formation. During the breakdown of glucose, this ratio is low; during fatty acid breakdown, this ratio is much higher. The longer the fatty acid, the higher the ratio and the higher the level of radical formation. This means that very long chain fatty acids should be broken down without generation of FADH₂ for mitochondria. This is accomplished in peroxisomes, thus explaining their role and evolution. The model explains many recent observations regarding radical formation by the respiratory chain. It also sheds light on the reasons for the lack of neuronal fatty acid (beta-) oxidation and for beneficial aspects of unsaturated fatty acids. Last but not least, it has very important implications for all models describing eukaryotic origins.

Mitonuclear interactions: evolutionary consequences over multiple biological scales

“…However, maximizing ATP production efficiency implies reducing heat production. Less evident, but equally important, the physiological role of hepatocyte mETS is substantially different to that of neurons, to the extent that neurons cannot use fatty acids as a fuel because they lack b-oxidation [106].…”

Evolution of peroxisomes illustrates symbiogenesis

“…The specific ROS generating site of complex I upon RET is still debated: The flavin containing site (I F ) [73] or the Q binding site (I Q ) [74] . Thus, the specific peroxisomal breakdown of VLCFAs makes perfect sense: using only these (which have the highest F/N ratios) the cell obtains a relatively strong reduction of the overall F/N ratio at minimal ATP loss [8]. When this kinetic theory of mitochondrial ROS formation was published, it was already known that two of the four recurring steps of peroxisomal FA oxidation were catalyzed by a single bi-functional enzyme (Pox2p; yeast nomenclature), of alphaproteobacterial (mitochondrial) origin, making the conclusion almost inescapable that peroxisomes indeed evolved after uptake of the endosymbiont [1].…”

“…Hence, reverse electron transport (RET; which depends on concomitant high membrane potentials (Dp) and QH 2 /Q ratios) would occur much more frequently during beta oxidation. The resulting ROS formation by complex I would lead to severe oxidative stress inside the newly merged pre-eukaryote [8]. This model (schematically depicted in Fig.…”

Brains have a gut feeling about fat storage

“…Leaving out one, that is gut reduction, in light of this newly observed negative correlation between brain and adipose tissue mass in mammals, seems premature at best. The negative correlation between brain size and fat storage can best be understood by the brain's vulnerability to oxygen radicals, a phenomenon precluding neuronal use of fatty acids for energy generation [5].…”

“…But most importantly, a better explanation for the observed (slight but consistent) overall inverse correlation exists. A straightforward reason is found in the biochemical fact that mammalian brains do not use fatty acid breakdown for energy generation [4], presumably because it gives rise to disproportionate oxygen radical formation [5]. Combined with the fact that mammals are not able to generate glucose from fatty acids [6,7], this nicely explains why relative fat use, and thus deposit size, decreases with increasing brain size.…”