How mitochondrial cristae illuminate the important role of oxygen during eukaryogenesis.

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.

The contours of evolution: In defence of Darwin's tree of life paradigm.

Both the concept of a Darwinian tree of life (TOL) and the possibility of its accurate reconstruction have been much criticized. Criticisms mostly revolve around the extensive occurrence of lateral gene transfer (LGT), instances of uptake of complete organisms to become organelles (with the associated subsequent gene transfer to the nucleus), as well as the implications of more subtle aspects of the biological species concept. Here we argue that none of these criticisms are sufficient to abandon the valuable TOL concept and the biological realities it captures. Especially important is the need to conceptually distinguish between organismal trees and gene trees, which necessitates incorporating insights of widely occurring LGT into modern evolutionary theory. We demonstrate that all criticisms, while based on important new findings, do not invalidate the TOL. After considering the implications of these new insights, we find that the contours of evolution are best represented by a TOL.

How mitochondria showcase evolutionary mechanisms and the importance of oxygen.

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.

How germline genes promote malignancy in cancer cells.

Cancers often express hundreds of genes otherwise specific to germ cells, the germline/cancer (GC) genes. Here, we present and discuss the hypothesis that activation of a "germline program" promotes cancer cell malignancy. We do so by proposing four hallmark processes of the germline: meiosis, epigenetic plasticity, migration, and metabolic plasticity. Together, these hallmarks enable replicative immortality of germ cells as well as cancer cells. Especially meiotic genes are frequently expressed in cancer, implying that genes unique to meiosis may play a role in oncogenesis. Because GC genes are not expressed in healthy somatic tissues, they form an appealing source of specific treatment targets with limited side effects besides infertility. Although it is still unclear why germ cell specific genes are so abundantly expressed in cancer, from our hypothesis it follows that the germline's reproductive program is intrinsic to cancer development.

Mitochondrial genomes revisited: why do different lineages retain different genes?

The mitochondria contain their own genome derived from an alphaproteobacterial endosymbiont. From thousands of protein-coding genes originally encoded by their ancestor, only between 1 and about 70 are encoded on extant mitochondrial genomes (mitogenomes). Thanks to a dramatically increasing number of sequenced and annotated mitogenomes a coherent picture of why some genes were lost, or relocated to the nucleus, is emerging. In this review, we describe the characteristics of mitochondria-to-nucleus gene transfer and the resulting varied content of mitogenomes across eukaryotes. We introduce a 'burst-upon-drift' model to best explain nuclear-mitochondrial population genetics with flares of transfer due to genetic drift.

RNA Editing in Mitochondria and Plastids: Weird and Widespread.

Though widespread, RNA editing is rare, except in endosymbiotic organelles. A combination of higher mutation rates, relaxation of energetic constraints, and high genetic drift is found within plastids and mitochondria and is conducive for evolution and expansion of editing processes, possibly starting as repair mechanisms. To illustrate this, we present an exhaustive phylogenetic overview of editing types.

Molecular characteristics of the multi-functional FAO enzyme ACAD9 illustrate the importance of FADH2 /NADH ratios for mitochondrial ROS formation.

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.

Eukaryotic cellular intricacies shape mitochondrial proteomic complexity.

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.

Neisseria meningitidis Sibling Small Regulatory RNAs Connect Metabolism with Colonization by Controlling Propionate Use.

Neisseria meningitidis (meningococcus) colonizes the human nasopharynx, primarily as a commensal, but sporadically causing septicemia and meningitis. During colonization and invasion, it encounters different niches with specific nutrient compositions. Small noncoding RNAs (sRNAs) are used to fine-tune expression of genes, allowing adaptation to their physiological differences. We have previously characterized sRNAs (Neisseria metabolic switch regulators [NmsRs]) controlling switches between cataplerotic and anaplerotic metabolism. Here, we extend the NmsR regulon by studying methylcitrate lyase (PrpF) and propionate kinase (AckA-1) involved in the methylcitrate cycle and serine hydroxymethyltransferase (GlyA) and 3-hydroxyacid dehydrogenase (MmsB) involved in protein degradation. These proteins were previously shown to be dysregulated in a ΔnmsRs strain. Levels of transcription of target genes and NmsRs were assessed by reverse transcriptase quantitative PCR (RT-qPCR). We also used a novel gene reporter system in which the 5' untranslated region (5' UTR) of the target gene is fused to mcherry to study NmsRs-target gene interaction in the meningococcus. Under nutrient-rich conditions, NmsRs downregulate expression of PrpF and AckA-1 by direct interaction with the 5' UTR of their mRNA. Overexpression of NmsRs impaired growth under nutrient-limiting growth conditions with pyruvate and propionic acid as the only carbon sources. Our data strongly suggest that NmsRs downregulate propionate metabolism by lowering methylcitrate enzyme activity under nutrient-rich conditions. Under nutrient-poor conditions, NmsRs are downregulated, increasing propionate metabolism, resulting in higher tricarboxylic acid (TCA) activities. IMPORTANCE Neisseria meningitidis colonizes the human nasopharynx, forming a reservoir for the sporadic occurrence of epidemic invasive meningococcal disease like septicemia and meningitis. Propionic acid generated by other bacteria that coinhabit the human nasopharynx can be utilized by meningococci for replication in this environment. Here, we showed that sibling small RNAs, designated NmsRs, riboregulate propionic acid utilization by meningococci and, thus, colonization. Under conditions mimicking the nasopharyngeal environment, NmsRs are downregulated. This leads to the conversion of propionic acid to pyruvate and succinate, resulting in higher tricarboxylic acid cycle activity, allowing colonization of the nasopharynx. NmsRs link metabolic state with colonization, which is a crucial step on the trajectory to invasive meningococcal disease.

Zombie ideas about early endosymbiosis: Which entry mechanisms gave us the "endo" in different endosymbionts?

Recently, a review regarding the mechanics and evolution of mitochondrial fission appeared in Nature. Surprisingly, it stated authoritatively that the mitochondrial outer membrane, in contrast with the inner membrane of bacterial descent, was acquired from the host, presumably during uptake. However, it has been known for quite some time that this membrane was also derived from the Gram-negative, alpha-proteobacterium related precursor of present-day mitochondria. The zombie idea of the host membrane still surrounding the endosymbiont is not only wrong, but more importantly, might hamper the proper conception of possible scenarios of eukaryogenesis. Why? Because it steers the imagination not only with regard to possible uptake mechanisms, but also regarding what went on before. Here I critically discuss both the evidence for the continuity of the bacterial outer membrane, the reasons for the persistence of the erroneous host membrane hypothesis and the wider implications of these misconceptions for the ideas regarding events occurring during the first steps towards the evolution of the eukaryotes and later major eukaryotic differentiations. I will also highlight some of the latest insights regarding different instances of endosymbiont evolution.

How neoteny shapes human society: Can we escape our formative years, and fight the wrong kind of populism?

This article describes aspects of our biological nature that have contributed to the dangerous current state of societal, ecological and climatological affairs. Next, it deals with stratagems to take these aspects into account, so as to allow us better choices. I will concentrate on the concepts of evolved group mechanisms and "neoteny" and explain why they direct our responses throughout our lives. The connection between our biological make-up and our vulnerability to the current rise of certain kinds of irrational, undemocratic, populism is also laid bare. I will end by listing some simple, but possibly controversial, proposals that might have value in combating these societal tendencies and help decision making in a reality-based, more scientific, manner.

Bad Faith Reasoning, Predictable Chaos, and the Truth.

Intelligent-design websites misquote to subvert belief in Darwinian evolution. Nowadays, such sites pose as "objective" sources of information. Speaking more generally, spreading misinformation can be linked to climate science denial, vaccination avoidance, and a resurgence of pseudo-scientific racism. Internet regulations to counter these sources of pseudo-science are urgently needed.

Debating Eukaryogenesis-Part 1: Does Eukaryogenesis Presuppose Symbiosis Before Uptake?

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.

Debating Eukaryogenesis-Part 2: How Anachronistic Reasoning Can Lure Us into Inventing Intermediates.

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.

Why Does the Web Seem to Bring Out the Best in Science but the Worst in Politics?

Reading Venki Ramakrishnan's "Gene Machine", describing the race to decipher the structure of the ribosome, inspired thoughts on the power of the internet: mostly for good in science, but often detrimental to society. Why is this so? The non-ideological nature of science holds part of the answer.

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.

AML-specific cytotoxic antibodies in patients with durable graft-versus-leukemia responses.

Most patients with acute myeloid leukemia (AML) can only be cured when allogeneic hematopoietic stem-cell transplantation induces a graft-versus-leukemia immune response (GVL). Although the role of T cells and natural killer cells in tumor immunology has been established, less is known about the contribution of B cells. From B cells of high-risk patients with AML with potent and lasting GVL responses, we isolated monoclonal antibodies directed against antigens expressed on the cell surface of AML cells but not on normal hematopoietic and nonhematopoietic cells. A number of these donor-derived antibodies recognized the U5 snRNP200 complex, a component of the spliceosome that in normal cells is found in the cell. In AML however, the U5 snRNP200 complex is exposed on the cell membrane of leukemic blasts. U5 snRNP200 complex-specific antibodies induced death of AML cells in an Fc receptor-dependent way in the absence of cytotoxic leukocytes or complement. In an AML mouse model, treatment with U5 snRNP200 complex-specific antibodies led to significant tumor growth inhibition. Thus, donor-derived U5 snRNP200 complex-recognizing AML-specific antibodies may contribute to antitumor responses.