Reconsidering ideas regarding the evolution of peroxisomes: the case for a mitochondrial connection

The article by Toni Gabaldón entitled “A metabolic scenario for the evolutionary origin of peroxisomes from the endomembranous system” that recently appeared in Cellular and Molecular Life Sciences [1] left me somewhat confused. In this article, the author proposes a model for the evolutionary origins of peroxisomes that can be described as follows: (1) peroxisomes are derived from the endoplasmic reticulum (ER); (2) the evolutionary forces driving the separation of peroxisomes from the ER stem from fatty acid metabolism in which certain reactions produce highly reactive toxic species, providing a strong selective force in favour of sequestering these reactions. Dr. Gabaldón states that such a hypothesis on the endomembranous origin of peroxisomes “has never been formally articulated in the context of a plausible evolutionary scenario describing the possible selective forces involved”. However, in 2010 I published an article which, in light of Dr. Gabaldón’s recent publication, has a surprising title: “Oxygen radicals shaping evolution: why fatty acid catabolism leads to peroxisomes while neurons do without it: FADH₂/NADH flux ratios determining mitochondrial radical formation were crucial for the eukaryotic invention of peroxisomes and catabolic tissue differentiation” [2]. As can be garnered from the title, the description of Dr. Gabaldón’s model given above, matches the model in my article (“eukaryotic invention” refers to the fact that peroxisomes coevolved with/are derived from the ER).

Are there differences? Yes, apart from shared characteristics, there is one fundamental difference between the two incarnations of the model: the cellular site at which oxygen radical formation during fatty acid metabolism leads to the selective force favouring peroxisome formation. Dr. Gabaldón believes that the cellular site is the ER, while I proposed the (pre)mitochondrion. This brings me to an important part of his article: his (implicit) arguments against my scenario. The most fundamental peroxisomal pathway is beta oxidation [its 4 steps catalysed sequentially by: an oxidase (step 1), a hydratase (step 2), a dehydrogenase (step 3) and a thiolase (step 4); performed by only three enzymes, with step 2 and 3 both being catalysed by a single protein, namely, Pox2p in yeast]. The three enzymes are all needed for complete oxidation, so the use of an “alpha-proteobacterial” Pox2p would strongly suggest the presence of the (pre)mitochondrion when peroxisomes were evolving. Surprisingly, the opposite conclusion is drawn by Dr. Gabaldón: “Hence, in contrast to earlier suggestions [25], this model does not necessarily imply that mitochondrial endosymbiosis pre-dated the origin of peroxisomes.” Of note, the “[25]” refers to my article—and is the only reference to my article. The presence of a “host” Pox1p for the first breakdown step is irrelevant in this regard, as it does not allow us to see whether the endosymbiont was already present or not. Also the next argument, namely, that the direct ER model is simpler because “…coupling the re-targeting of mitochondrial enzymes to the formation of peroxisomes implies that these enzymes were targeted first to the ER…”, is unconvincing. First of all, such re-targeting has been documented many times, showing it to be no big hurdle. Secondly, new endomembrane formations, such as the nucleus, the ER and peroxisomes, can be seen as “reactions” to the problems generated by endosymbiont entry; consequently, the presence of a full blown ER with specific targeting signals when peroxisomes originated is not that likely. Stressing adaptations to the endosymbiont as the basis of the eukaryotic lineage is a common theme my model shares with reports by other authors, such as Martin and Koonin’s hypothesis regarding the development of the nucleus (and thus, the ER) in response to alphaproteobacterial group II introns ending up in the host genome [3]. Seen like this the evolution of peroxisomes is only (an exciting) part of the intricate repatterning necessary for the development of the first eukaryote.

Dr. Gabaldón spends a lot of effort and space stating that peroxisomes are a eukaryotic invention, derived from the ER. Nobody doubts this any longer. Beautiful experimental work by many groups, but especially by Tabak and colleagues, led me to state in my 2010 article: “…convincingly establishes the peroxisome as a eukaryotic invention” [2]. Since then, the further discovery that peroxisomes form via heterotypic fusion of distinct ER derived preperoxisomal vesicles [4], referenced in Dr. Gabaldón’s article, makes that part of the discussion superfluous. Let me end by highlighting some other observations that my model also seems to explain. I generated a testable model as to how fatty acid metabolism could give rise to oxygen radicals in mitochondria. Dr. Gabaldón provides no explanation for the appearance of “highly reactive species” in the ER. Thus far we always find peroxisomes and mitochondria together, with amitochondriate species, such as Giardia Lamblia, also missing peroxisomes. Rare exceptions, such as the apicomplexans, combine the loss of peroxisomes with extremely reduced mitochondrial function (beta oxidation is absent). Later eukaryotic developments in plants and most yeasts saw all beta oxidation migrate from mitochondria to peroxisomes, further reducing the possibilities for mitochondrial radical formation. Mammalian mitochondria and peroxisomes also exhibit extensive crosstalk. This all makes sense in the light of my model [2] but can not be explained by the “ER model”.

In conclusion, Dr. Gabaldón’s new model is, for the most part, not new, and the part that is is not supported by the arguments he makes.