Mitochondria have been fundamental to the eco‐physiological success of eukaryotes since the last eukaryotic common ancestor (LECA). They contribute essential functions to eukaryotic cells, above and beyond classical respiration. Mitochondria interact with, and complement, metabolic pathways occurring in other organelles, notably diversifying the chloroplast metabolism of photosynthetic organisms. Here, we integrate existing literature to investigate how mitochondrial metabolism varies across the landscape of eukaryotic evolution. We illustrate the mitochondrial remodelling and proteomic changes undergone in conjunction with major evolutionary transitions. We (...) explore how the mitochondrial complexity of the LECA has been remodelled in specific groups to support subsequent evolutionary transitions, such as the acquisition of chloroplasts in photosynthetic species and the emergence of multicellularity. We highlight the versatile and crucial roles played by mitochondria during eukaryotic evolution, extending from its huge contribution to the development of the LECA itself to the dynamic evolution of individual eukaryote groups, reflecting both their current ecologies and evolutionary histories. (shrink)

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. (shrink)

Eukaryotic origins are inextricably linked with the arrival of a pre‐mitochondrion of alphaproteobacterial‐like ancestry. However, the nature of the “host” cell and the mode of entry are subject to heavy debate. It is becoming clear that the mutual adaptation of a relatively simple, archaeal host and the endosymbiont has been the defining influence at the beginning of the eukaryotic lineage; however, many still resist such symbiogenic models. In part 1, it is posited that a symbiotic stage before uptake (“pre‐symbiosis”) seems (...) essential to allow further metabolic integration of the two partners ending in endosymbiosis. Thus, the author argued against phagocytic mechanisms (in which the bacterium is prey or parasite) as the mode of entry. Such positions are still broadly unpopular. Here it is explained why. Evolutionary thinking, especially in the case of eukaryogenesis, is still dominated by anachronistic reasoning, in which highly derived protozoan organisms are seen as in some way representative of intermediate steps during eukaryotic evolution, hence poisoning the debate. This reasoning reflects a mind‐set that ignores that Darwinian evolution is a fundamentally historic process. Numerous examples of this kind of erroneous reasoning are given, and some basic precautions against its use are formulated. Also see the video abstract here https://youtu.be/ekqtNleVJpU. (shrink)

Recently, constructive neutral evolution has been touted as an important concept for the understanding of the emergence of cellular complexity. It has been invoked to help explain the development and retention of, amongst others, RNA splicing, RNA editing and ribosomal and mitochondrial respiratory chain complexity. The theory originated as a welcome explanation of isolated small scale cellular idiosyncrasies and as a reaction to ‘overselectionism’. Here I contend, that in its extended form, it has major conceptual problems, can not explain observed (...) patterns of complex processes, is too easily dismissive of alternative selectionist models, underestimates the creative force of complexity as such, and – if seen as a major evolutionary mechanism for all organisms – could stifle further thought regarding the evolution of highly complex biological processes. (shrink)

Eukaryotic origins are heavily debated. The author as well as others have proposed that they are inextricably linked with the arrival of a pre‐mitochondrion of alphaproteobacterial‐like ancestry, in a so‐called symbiogenic scenario. The ensuing mutual adaptation of archaeal host and endosymbiont seems to have been a defining influence during the processes leading to the last eukaryotic common ancestor. An unresolved question in this scenario deals with the means by which the bacterium ends up inside. Older hypotheses revolve around the application (...) of known antagonistic interactions, the bacterium being prey or parasite. Here, in reviewing the field, the author argues that such models share flaws, hence making them less likely, and that a “pre‐symbiotic stage” would have eased ongoing metabolic integration. Based on this the author will speculate about the nature of the (endo) symbiosis that started eukaryotic evolution–in the context of bacterial entry being a relatively “early” event–and stress the differences between this uptake and subsequent ones. He will also briefly discuss how the mutual adaptation following the merger progressed and how many eukaryotic hallmarks can be understood in light of coadaptation. Also see the video abstract here https://youtu.be/ekqtNleVJpU. (shrink)

Inner membranes of mitochondria are extensively folded, forming cristae. The observed overall correlation between efficient eukaryotic ATP generation and the area of internal mitochondrial inner membranes both in unicellular organisms and metazoan tissues seems to explain why they evolved. However, the crucial use of molecular oxygen (O2) as final acceptor of the electron transport chain is still not sufficiently appreciated. O2 was an essential prerequisite for cristae development during early eukaryogenesis and could be the factor allowing cristae retention upon loss (...) of mitochondrial ATP generation. Here I analyze illuminating bacterial and unicellular eukaryotic examples. I also discuss formative influences of intracellular O2 consumption on the evolution of the last eukaryotic common ancestor (LECA). These considerations bring about an explanation for the many genes coming from other organisms than the archaeon and bacterium merging at the start of eukaryogenesis. (shrink)

A decade ago I postulated that ROS formation in mitochondria was influenced by different FADH2/NADH (F/N) ratios of catabolic substrates. Thus, fatty acid oxidation (FAO) would give higher ROS formation than glucose oxidation. Both the emergence of peroxisomes and neurons not using FAO, could be explained thus. ROS formation in NADH:ubiquinone oxidoreductase (Complex I) comes about by reverse electron transport (RET) due to high QH2 levels, and scarcity of its electron‐acceptor (Q) during FAO. The then new, unexpected, finding of an (...) FAO enzyme, ACAD9, being involved in complex I biogenesis, hinted at connections in line with the hypothesis. Recent findings about ACAD9's role in regulation of respiration fit with predictions the model makes: cementing connections between ROS production and F/N ratios. I describe how ACAD9 might be central to reversing the oxidative damage in complex I resulting from FAO. This seems to involve two distinct, but intimately connected, ACAD9 characteristics: (i) its upregulation of complex I biogenesis, and (ii) releasing FADH2, with possible conversion into FMN, the crucial prosthetic group of complex I. Also see the video abstract here: https://youtu.be/N7AT_HBNumg. (shrink)

Darwinian evolution can be simply stated: natural selection of inherited variations increasing differential reproduction. However, formulated thus, links with biochemistry, cell biology, ecology, and population dynamics remain unclear. To understand interactive contributions of chance and selection, higher levels of biological organization (e.g., endosymbiosis), complexities of competing selection forces, and emerging biological novelties (such as eukaryotes or meiotic sex), we must analyze actual examples. Focusing on mitochondria, I will illuminate how biology makes sense of life's evolution, and the concepts involved. First, (...) looking at the bacterium – mitochondrion transition: merging with an archaeon, it lost its independence, but played a decisive role in eukaryogenesis, as an extremely efficient aerobic ATP generator and internal ROS source. Second, surveying later mitochondrion adaptations and diversifications illustrates concepts such as constructive neutral evolution, dynamic interactions between endosymbionts and hosts, the contingency of life histories, and metabolic reprogramming. Without oxygen, mitochondria disappear; with (intermittent) oxygen diversification occurs in highly complex ways, especially upon (temporary) phototrophic substrate supply. These expositions show the Darwinian model to be a highly fruitful paradigm. (shrink)

Recently, the group of McBride reported a stunning observation regarding peroxisome biogenesis: newly born peroxisomes are hybrids of mitochondrial and ER-derived pre-peroxisomes. What was stunning? Studies performed with the yeast Saccharomyces cerevisiae had convincingly shown that peroxisomes are ER-derived, without indications for mitochondrial involvement. However, the recent finding using fibroblasts dovetails nicely with a mechanism inferred to be driving the eukaryotic invention of peroxisomes: reduction of mitochondrial reactive oxygen species generation associated with fatty acid oxidation. This not only explains the (...) mitochondrial involvement, but also its apparent absence in yeast. The latest results allow a reconstruction of the evolution of the yeast's highly derived metabolism and its limitations as a model organism in this instance. As I review here, peroxisomes are eukaryotic inventions reflecting mutual host endosymbiont adaptations: this is predicted by symbiogenetic theory, which states that the defining eukaryotic characteristics evolved as a result of mutual adaptations of two merging prokaryotes. See also the video abstract here: https://youtu.be/HtyKhQ3DSxg Eukaryotic peroxisomes illustrate effects of symbiogenesis, following the non-phagocytotic merger of an archaeon and a bacterium. Internal ROS formation upon fatty acid oxidation was reduced by the invention of peroxisomes for extra-mitochondrial FA oxidation. Both peroxisomal membranes and their oldest enzymes seem ultimately derived from the pre-mitochondrion. (shrink)

Of two contending models for eukaryotic evolution the “archezoan“ has an amitochondriate eukaryote take up an endosymbiont, while “symbiogenesis“ states that an Archaeon became a eukaryote as the result of this uptake. If so, organelle formation resulting from new engulfments is simplified by the primordial symbiogenesis, and less informative regarding the bacterium‐to‐mitochondrion conversion. Gradualist archezoan visions still permeate evolutionary thinking, but are much less likely than symbiogenesis. Genuine amitochondriate eukaryotes have never been found and rapid, explosive adaptive periods characteristic of (...) symbiogenetic models explain this. Mitochondrial proteomes, encoded by genes of “eukaryotic origin“ not easily linked to host or endosymbiont, can be understood in light of rapid adjustments to new evolutionary pressures. Symbiogenesis allows “expensive” eukaryotic inventions via efficient ATP generation by nascent mitochondria. However, efficient ATP production equals enhanced toxic internal ROS formation. The synergistic combination of these two driving forces gave rise to the rapid evolution of eukaryotes.Also watch the Video Abstract. (shrink)

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. (shrink)

I hypothesize that the appearance of sex facilitated the merging of the endosymbiont and host genomes during early eukaryote evolution. Eukaryotes were formed by symbiosis between a bacterium that entered an archaeon, eventually giving rise to mitochondria. This entry was followed by the gradual transfer of most bacterial endosymbiont genes into the archaeal host genome. I argue that the merging of the mitochondrial genes into the host genome was vital for the evolution of genuine eukaryotes. At the time this process (...) commenced it was unprecedented and required a novel mechanism. I suggest that this mechanism was meiotic sex, and that its appearance might have been THE crucial step that enabled the evolution of proper eukaryotes from early endosymbiont containing proto‐eukaryotes. Sex might continue to be essential today for keeping genome insertions in check. Also see the video abstract here: https://youtu.be/aVMvWMpomac. (shrink)

Beta‐oxidation of fatty acids and detoxification of reactive oxygen species are generally accepted as being fundamental functions of peroxisomes. Additionally, these pathways might have been the driving force favoring the selection of this compartment during eukaryotic evolution. Here we performed phylogenetic analyses of enzymes involved in beta‐oxidation of fatty acids in Bacteria, Eukaryota, and Archaea. These imply an alpha‐proteobacterial origin for three out of four enzymes. By integrating the enzymes' history into the contrasting models on the origin of eukaryotic cells, (...) we conclude that peroxisomes most likely evolved non‐symbiotically and subsequent to the acquisition of mitochondria in an archaeal host cell. (shrink)