Molecules are transferred to lysosomes, the major, acid pH, digestive compartment in eukaryotic cells, by a complex series of pathways that converge at a late endosome/prelysosomal compartment. Here, we discuss the relationship between this compartment and the lysosome. We propose that lysosomes are maintained within cells by a repeated series of kiss and run, transient fusion and fission processes with the late endosome/prelysosome compartment. Directionality to these processes may be conferred by pH gradients and retrieval mechanisms. The future challenge in (...) testing this and any other proposed hypothesis for lysosomal biogenesis will be the establishment of molecular mechanisms. (shrink)

Peroxisomes are eukaryotic organelles that are the subcellular location of important metabolic reactions. In humans, defects in the organelle's function are often lethal. Yet, relative to other organelles, little is known about how cells maintain and propagate peroxisomes or how they direct specific sets of newly synthesized proteins to these organelles (peroxisome biogenesis/assembly). In recent years, substantial progress has been made in elucidating aspects of peroxisome biogenesis and in identifying PEX genes whose products, peroxins, are essential for one (...) or more of these processes. The most progress has been made in understanding the mechanism by which peroxisome matrix proteins are imported into the organelles. Signal sequences responsible for targeting proteins to the organelle have been defined. Potential signal receptor proteins, a receptor docking protein and other components of the import machinery have been identified, along with insights into how they operate. These studies indicate that multiple peroxisomal protein‐import mechanisms exist and that these mechanisms are novel, not simply variations of those described for other organelles. (shrink)

A recent paper by Nisoli et al.1 provides the first evidence that elevated levels of nitric oxide (NO) stimulate mitochondrial biogenesis in a number of cell lines via a soluble guanylate‐cyclase‐dependent signaling pathway that activates PGC1α (peroxisome proliferator‐activated receptor γ coactivator‐1α), a master regulator of mitochondrial content. These results raise intriguing possibilities for a role of NO in modulating mitochondrial content in response to physiological stimuli such as exercise or cold exposure. However, whether this signaling cascade represents a widespread (...) mechanism by which mammalian tissues regulate mitochondrial content, and how it might integrate with other pathways that control PGC1α expression, remain unclear. BioEssays 25:538–541, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The fall of the nineteenth century abounded in discoveries of natural laws, that is, strict and unequivocal rules of the development of life. These laws stated for example that ontogeny of individuals repeats, or recapitulates, phylogeny of the species; that big and specialized forms originate in evolution from small and unspecialized ones, while the reverse is not true; that endothermic animals are larger-sized and more compact in cool than in warm climates, and so on. Louis Dollo, a Belgian palaeontologist, proposed (...) the so-called law of irreversibility of evolution which stated that an organic structure lost in evolution cannot reappear with all the peculiarities of its design. This law seems indeed to be true but not particularly original. It was Heraclitus who first observed that one could not enter the same river twice. Dollo's law says essentially the same thing. The flow of evolutionary events combines so many processes in so many ways that past evolutionary events cannot recur exactly. “What is done, is done forever”. Time itself introduces asymmetry into the evolutionary process. (shrink)

Outer membrane proteins (OMPs) maintain the viability of Gram‐negative bacteria by functioning as receptors, transporters, ion channels, lipases, and porins. Folding and assembly of OMPs involves synchronized action of chaperones and multi‐protein machineries which escort the highly hydrophobic polypeptides to their target outer membrane in a folding competent state. Previous studies have identified proteins and their involvement along the OMP biogenesis pathway. Yet, the mechanisms of action and the intriguing ability of all these molecular machines to work without the (...) typical cellular energy source of ATP, but solely based on thermodynamic principles, are still not well understood. Here, we highlight how different single‐molecule studies can shed additional light on the mechanisms and kinetics of OMP biogenesis. (shrink)

No evidence exists that the accidental origin of life is too improbable to have occurred naturally, but there are numerous attempts to argue so. Dizzying statistics are cited to show that a god had to be responsible. This paper identifies the Argument from Biogenesis, then explains why all these arguments so far fail, and what would actually have to be done to make such an argument succeed. Describes seven general types of error, with examples. Includes a table of forty-seven (...) statistics used by over twenty authors to date. (shrink)

The Gram-negative outer membrane is a potent permeability barrier against antibiotics, limiting clinical options amid mounting rates of resistance. The Lol transport pathway delivers lipoproteins to the OM. All the OM assembly machines require one or more OM lipoprotein to function, making the Lol pathway central for all aspects of OM biogenesis. The Lol pathways of many medically important species clearly deviate from the Escherichia coli paradigm, perhaps with implications for efforts to develop novel antibiotics. Moreover, recent work reveals (...) the existence of an undiscovered alternate route for bringing lipoproteins to the OM. Here, lipoprotein transport mechanisms, and the quality control systems that underpin them, is re-examined in context of their diversity. All essential outer membrane assembly machines require lipoproteins to function. Hence, the transport mechanisms supplying these lipoproteins are critical for maintaining the integrity of the outer membrane barrier against antibiotics. Lipoprotein transport strategies of diverse Gram-negative bacteria will be reviewed in the context of recent discoveries. (shrink)

The fate of eukaryotic proteins, from their synthesis to destruction, is supervised by the ubiquitin–proteasome system (UPS). The UPS is the primary pathway responsible for selective proteolysis of intracellular proteins, which is guided by covalent attachment of ubiquitin to target proteins by E1 (activating), E2 (conjugating), and E3 (ligating) enzymes in a process known as ubiquitylation. The UPS can also regulate protein synthesis by influencing multiple steps of RNA (ribonucleic acid) metabolism. Here, recent publications concerning the interplay between the UPS (...) and different types of RNA are reviewed. This interplay mainly involves specific RNA‐binding E3 ligases that link RNA‐dependent processes with protein ubiquitylation. The emerging understanding of their modes of RNA binding, their RNA targets, and their molecular and cellular functions are primarily focused on. It is discussed how the UPS adapted to interact with different types of RNA and how RNA molecules influence the ubiquitin signaling components. (shrink)

The polarized organization of epithelial cells is expressed in many ways including the morphology of the cell surface or cytocortex, the molecular composition of membrane domains and the distribution of cytoplasmic organelles. The differentiation of mouse trophectoderm is described with particular attention given to the maturation of the endocytic system in an attempt to define how the complex assembly of an epithelium may be generated.

From stem cells to oocyte, Drosophila germ cells undergo a short, defined lineage. Molecular genetic analyses of a collection of female sterile mutations have indicated that a germ cell‐specific organelle called the fusome has a central role at several steps in this lineage. The fusome grows from a prominent spherical organelle to an elongated and branched structure that connects all mitotic sisters in a germ cell syncytium. The organelle is assembled from proteins normally found in the membrane skeleton and, additionally, (...) contains an extensive membranous reticulum, the probable product of differentiation‐dependent vesicle trafficking. This review briefly summarizes a current view of the processes that drive germ cell differentiation, particularly the various roles that the fusome might play in regulating the developmental events. Future efforts will consider to what extent an organelle assembly‐dependent model for differentiation is heuristic and whether the Drosophila fusome represents a homolog of a similar organelle in vertebrate lymphocytes. (shrink)

The question of the origin of life interested people for centuries. All existing views on this subject can be classified into different areas of our knowledge of the world: natural sciences, philosophy, and theology. Some theories contain more or less explicit elements from all of these areas. Thus, it is helpful to take a closer look at them and to classify all the typical groups of theories about the origins of life. We can in this way stress their mutual connections (...) and clarify their own nature. Nowadays, driving forces of pre-biological chemical evolution and the explanation of the transition from “non-life into life” present a great variety of solutions. The differences between the theories, however, as well as the current controversies in the scientific community, will be shown to be of secondary importance in comparison with several much more profound philosophical assumptions underlying the origin-of-life-studies. The attempt to organize and classify different types of theories on the genesis of life allows to take into account different kinds of perspectives, and to compare them to each other. The most general division between theories is based on a distinction between metaphysical conceptions and scientific ones. Some theories answer the question of the emergence of life in general, whereas others tackle the question of the origin of life on Earth only. Interestingly, two traditional ideas concerning the problem of the origin of life are still at play in contemporary scientific research, albeit in a modified form. In the perspective of contemporary scientific research on the origin of life it seems interesting that two main ideas concerning the problem of the origin of life, spontaneous generation and panspermia, are still present as presuppositions of certain theories but have been modified. Moreover, it is evident that the theistic view of the origin of life does not have to fall into conflict with contemporary scientific theories. Rather, they are complementary. This article is an extension, explanation and refinement of the proposed scheme of the main types of theories on the origin of life. An attempt to classify various biogenesis theories is also proposed. One of the most important questions that will be addressed concerns the philosophical presumptions of biogenetics still informing current research as well as scientific explanations of the origin of life. (shrink)

The lysosome serves as a site for delivery of materials targeted for removal from the eukaryotic cell. The mechanisms underlying the biogenesis of this organelle are currently the subject of renewed interest due to advances in our understanding of the protein sorting machinery. Genetic model systems such as yeast and Drosophila have been instrumental in identifying both protein and lipid components of this machinery. Importantly, many of these components, as well as the processes in which they are involved, are (...) proving conserved in mammals. Other recently identified components, however, appear to be unique to higher eukaryotes. BioEssays 23:333–343, 2001. Published 2001 John Wiley & Sons, Inc. (shrink)

Endosomes, which comprise a diverse population of membrane vesicles and tubules, sort proteins and lipids to various cellular destinations. The organization and functions of these pleiomorphic cellular organelles have been extensively studied. Matsuo et al.1 now provide new exciting evidence on the role of lysobiphosphatidic acid (LBPA), a resident phospholipid of internal vesicles of the late endosome, in the control of membrane invagination and endosome biogenesis. In vivo, LBPA functions are controlled by the adaptor protein Alix and depend on (...) pH gradients along the endosomal compartments. BioEssays 26:604–607, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The Arf family proteins are best known for their roles in the vesicle biogenesis. However, they also play fundamental roles in a wide range of cellular regulation besides vesicular trafficking, such as modulation of lipid metabolic enzymes, cytoskeleton remodeling, ciliogenesis, lysosomal, and mitochondrial morphology and functions. Growing studies continue to expand the downstream effector landscape of Arf proteins, especially for the less‐studied members, revealing new biological functions, such as amino acid sensing. Experiments with cutting‐edge technologies and in vivo functional (...) studies in the last decade help to provide a more comprehensive view of Arf family functions. In this review, we summarize the cellular functions that are regulated by at least two different Arf members with an emphasis on those beyond vesicle biogenesis. (shrink)

The coupling of protein synthesis and folding is a crucial yet poorly understood aspect of cellular protein folding. Over the past few years, it has become possible to experimentally follow and define protein folding on the ribosome, revealing principles that shape co‐translational folding and distinguish it from refolding in solution. Here, we highlight some of these recent findings from biochemical and biophysical studies and their potential significance for cellular protein biogenesis. In particular, we focus on nascent chain interactions with (...) the ribosome, interactions within the nascent protein, modulation of translation elongation rates, and the role of mechanical force that accompanies nascent protein folding. The ability to obtain mechanistic insight in molecular detail has set the stage for exploring the intricate process of nascent protein folding. We believe that the aspects discussed here will be generally important for understanding how protein synthesis and folding are coupled and regulated. (shrink)

Ribosome biogenesis includes the making and processing of ribosomal RNAs, the biosynthesis of ribosomal proteins from their mRNAs in the cytosol and their transport to the nucleolus to assemble pre‐ribosomal particles. Several stresses including cellular senescence reduce nucleolar rRNA synthesis and maturation increasing the availability of ribosome‐free ribosomal proteins. Several ribosomal proteins can activate the p53 tumor suppressor pathway but cells without p53 can still arrest their proliferation in response to an imbalance between ribosomal proteins and mature rRNA production. (...) Recent results on senescence‐associated ribogenesis defects (SARD) show that the ribosomal protein S14 (RPS14 or uS11) can act as a CDK4/6 inhibitor linking ribosome biogenesis defects to the main engine of cell cycle progression. This work offers new insights into the regulation of the cell cycle and suggests novel avenues to design anticancer drugs. (shrink)

Over the last decade, our appreciation of the importance of the nucleolus for cellular function has progressed from the ordinary to the extraordinary. We no longer think of the nucleolus as simply the site of ribosome production, or a dynamic subnuclear body noted by pathologists for its changes in size and shape with malignancy. Instead, the nucleolus has emerged as a key controller of many cellular processes that are fundamental to normal cell homeostasis and the target for dysregulation in many (...) human diseases; in some cases, independent of its functions in ribosome biogenesis. These extra‐nucleolar or new functions, which we term “non‐canonical” to distinguish them from the more traditional role of the nucleolus in ribosome synthesis, are the focus of this review. In particular, we explore how these non‐canonical functions may provide novel insights into human disease and in some cases new targets for therapeutic development. (shrink)

Lipid droplets (LDs) are ubiquitous, neutral lipid storage organelles that act as hubs of metabolic processes. LDs are structurally unique with a hydrophobic core that mainly consists of neutral lipids, sterol esters, and triglycerides, enclosed within a phospholipid monolayer. Nascent LD formation begins with the accumulation of neutral lipids in the endoplasmic reticulum (ER) bilayer. The ER membrane proteins such as seipin, LDAF1, FIT, and MCTPs are reported to play an important role in the formation of nascent LDs. As the (...) LDs grow, they unmix from the highly charged ER membrane to form mature LDs. LD biogenesis is an exciting, emerging research area, and herein, we discuss the recent progress in our understanding of the formation of eukaryotic nascent LDs. We focus on the role of ER membrane shaping proteins such as reticulons and reticulon‐like proteins, membrane lipids, and cytoskeleton proteins such as septin in the formation of nascent LDs. (shrink)

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the (...) biogenesis of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. Are randomly generated mutations the only source of genetic variation during evolution? This paper describes the molecular mechanisms by which co-transcriptional and co-translational biophysical constraints trigger genetic variations in targeted-genomic sequences in an RNA-depending manner. This directed-mutational process that drives genome evolution is related to antiparasite genome defence systems. (shrink)

Mitochondrial function and biogenesis depend on the transport of a large variety of proteins, ions, and metabolites across the two surrounding membranes. While several specific transporters are present in the inner membrane, transport processes across the outer membrane are less understood. Recent studies reveal that the number of outer membrane channels and their transport mechanisms are more diverse than originally thought. Four protein‐conducting channels promote transport of distinct sets of precursor proteins across and into the outer membrane. The voltage‐dependent (...) anion channel (VDAC) forms the major channel for small hydrophilic molecules. In addition, three channels with yet unknown substrate specificity exist in the outer membrane. In this review, we outline the emerging functional diversity, selectivity, and regulation of mitochondrial outer membrane channels. The presence of several channel‐forming proteins challenges the traditional view that the outer membrane forms an unspecific size‐exclusion filter for the flux of small hydrophilic molecules. (shrink)

David Hume's famous riddle of induction implies a second problem related to the question of whether the laws and principles of nature might change in the course of time. Claims have been made that modern developments in physics and astrophysics corroborate the translational invariance of the laws of physics in time. However, the appearance of a new general principle of nature, which might not be derivable from the known laws of physics, or that might actually be a non-physical one (this (...) means completely independent of physical science) supports the notion that the course of nature can change in time. Here it is argued that natural selection satisfies the criteria that identify a general principle of nature which so far, appears to be non-derivable from the known laws of physics and therefore, it is likely that it arose in the course of time, thus leaving open again the quest for a true solution to Hume's second problem. (shrink)

If the problem of the origin of life is conceptualized as a process of emergence of biochemistry from proto-biochemistry, which in turn emerged from the organic chemistry and geochemistry of primitive earth, then the resources of the new sciences of complex systems dynamics can provide a more robust conceptual framework within which to explore the possible pathways of chemical complexification leading to living systems and biosemiosis. In such a view the emergence of life, and concomitantly of natural selection and biosemiosis, (...) is the result of deep natural laws (the outlines of which we are only beginning to perceive) and reflects a degree of holism in those systems that led to life. Further, such an approach may lead to the development of a more general theory of biology and of natural organization, one informed by semiotic concepts. (shrink)

Microtubules are protein cylinders with functions in cell motility, signal sensing, cell organization, intracellular transport, and chromosome segregation. One of the key properties of microtubules is their dynamic architecture, allowing them to grow and shrink in length by adding or removing copies of their basic subunit, the heterodimer αβ‐tubulin. In higher eukaryotes, de novo assembly of microtubules from αβ‐tubulin is initiated by a 2 MDa multi‐subunit complex, the gamma‐tubulin ring complex (γ‐TuRC). For many years, the structure of the γ‐TuRC and (...) the function of its subunits remained enigmatic, although structural data from the much simpler yeast counterpart, the γ‐tubulin small complex (γ‐TuSC), were available. Two recent breakthroughs in the field, high‐resolution structural analysis and recombinant reconstitution of the complex, have revolutionized our knowledge about the architecture and function of the γ‐TuRC and will form the basis for addressing outstanding questions about biogenesis and regulation of this essential microtubule organizer. (shrink)

: The oft-repeated claim that life is ‘ written into ’ the laws of nature is examined and criticised. Arguments are given in favour of life spreading between near-neighbour planets in rocky impact ejecta (transpermia), but against panspermia, leading to the conclusion that if life is indeed found to be widespread in the universe, some form of life principle or biological determinism must be at work in the process of biogenesis. Criteria for what would constitute a credible life principle (...) are elucidated. I argue that the key property of life is its information content, and speculate that the emergence of the requisite information-processing machinery might require quantum information theory for a satisfactory explanation. Some clues about how decoherence might be evaded are discussed. The implications of some of these ideas for ‘ fine-tuning ’ are discussed. (shrink)

The transient cellular organelles known as migrasomes, which form during cell migration along retraction fibers, have emerged as a crutial factor in various fundamental cellular processes and pathologies. These membrane vesicles originate from local membrane swellings, encapsulate specific cytoplasmic content, and are eventually released to the extracellular environment or taken up by recipient cells. Migrasome biogenesis entails a sequential membrane remodeling process involving a complex interplay between various molecular factors such as tetraspanin proteins, and mechanical properties like membrane tension (...) and bending rigidity. In this review, we summarize recent studies exploring the mechanism of migrasome formation. We emphasize how physical forces, together with molecular factors, shape migrasome biogenesis, and detail the involvement of migrasomes in various cellular processes and pathologies. A comprehensive understanding of the exact mechanism underlying migrasome formation and the identification of key molecules involved hold promise for advancing their therapeutic and diagnostic applications. (shrink)

The Type VI secretion system is a multiprotein and mosaic apparatus that delivers protein effectors into prokaryotic or eukaryotic cells. Recent data on the enteroaggregative Escherichia coli T6SS have provided evidence that the TssA protein is a key component during T6SS biogenesis. The T6SS comprises a trans-envelope complex that docks the baseplate, a cytoplasmic complex that represents the assembly platform for the tail. The T6SS tail is structurally, evolutionarily and functionally similar to the contractile tails of bacteriophages. We have (...) shown that TssA docks to the membrane complex, recruits the baseplate complex and initiates and coordinates the polymerization of the inner tube with that of the sheath. Here, we review these recent findings, discuss the variations within TssA-like proteins, speculate on the role of EAEC TssA in T6SS biogenesis and propose future research perspectives. In the environment, bacteria have to cope with other microbial species and therefore have evolved anti-microbial mechanisms. The bacterial Type VI secretion system transports toxins into bacterial and/or eukaryotic cells using a contractile mechanism. At the architectural level, the T6SS could be viewed as a nano-speargun assembled in the bacterial cytoplasm and anchored to a trans-envelope complex. We describe and speculate on recent findings demonstrating that the TssA subunit is involved in the different stages of T6SS biogenesis. (shrink)

Chance has somewhat different meanings in different contexts, and can be taken to be either ontological or epistemological . Here I argue that, whether or not it stems from physical indeterminacy, chance is a fundamental biological reality that is meaningless outside the context of knowledge. To say that something happened by chance means that it did not happen by design. This of course is a cornerstone of Darwin’s theory of evolution: random undirected variation is the creative wellspring upon which natural (...) selection acts to sculpt the functional form of organisms. In his essay Chance & Necessity, Jacques Monod argued that an intellectually honest commitment to objectivity requires that we accord chance a central role in an otherwise mechanistic biology, and suggested that doing so may well place the origin of life outside the realm of scientific tractability. While that may be true, ongoing research on the origin of life problem suggests that a biogenesis may have been possible, and perhaps even probable, under the conditions that existed on primordial earth. Following others, I argue that the world should be viewed as causally open, i.e. primordially indeterminate or vague. Accordingly, chance ought to be the default scientific explanation for origination, a universal ‘null hypothesis’ to be assumed until disproven. In this framework, creation of anything new manifests freedom , and causation manifests constraint, the developmental emergence of which establishes the space of possibilities that may by chance be realized. (shrink)

Emerging evidence suggests that microRNA (miRNA)‐mediated post‐transcriptional gene regulation plays an essential role in modulating embryonic stem (ES) cell pluripotency maintenance, differentiation, and reprogramming of somatic cells to an ES cell‐like state. Investigations from ES cell‐enriched miRNAs, such as mouse miR‐290 cluster and human miR‐302 cluster, and ES cell‐depleted miRNAs such as let‐7 family miRNAs, revealed a common theme that miRNAs target diverse cellular processes including cell cycle regulators, signaling pathway effectors, transcription factors, and epigenetic modifiers and shape their protein (...) output. The combinatorial effects downstream of miRNA action allow miRNAs to modulate cell‐fate decisions effectively. Furthermore, the transcription and biogenesis of miRNAs are also tightly regulated. Thus, elucidating the interplay between miRNAs and other modes of gene regulation will shed new light on the biology of pluripotent stem cells and somatic cell reprogramming. (shrink)

One of the most influential physics books of the twentieth century was actually about biology. In a series of lectures, Erwin Schrödinger described how he believed that quantum mechanics, or some variant of it, would soon solve the riddle of life. These lectures were published in 1944 under the title What is life? and are credited by some as ushering in the age of molecular biology. In the nineteenth century, many scientists thought they knew the answer to Schrödinger’s rhetorical question. (...) Life, they maintained, was some sort of magic matter. The continued use of the term ‘organic chemistry’ is a hangover from that era. The belief that there is a chemical recipe for life led to the hope that, if only we knew what it was, we could mix up the right stuff in a test tube and make life in the lab. Most research on biogenesis has followed that tradition, by assuming that chemistry was a bridge — and a long one at that — linking matter with life. Elucidating this chemical pathway has been a tantalizing goal, spurred on by the famous Miller–Urey experiment of 1952, in which amino acids were made by sparking electricity through a mixture of water and common gases. But the concept has turned out to be something of a blind alley, and further progress with prebiotic chemical synthesis has been frustratingly slow. The origin of life remains one of the great outstanding mysteries of science. To take up Schrödinger’s suggestion, a radical solution to the problem, ‘What is life?’ could be that quantum mechanics enabled life to emerge directly from the atomic world, without the need for complex intermediate chemistry. Life must have a chemical basis: organic molecules provide the hardware for biology. But what about the software? When Schrödinger asked, ‘What is life?’ he could already glimpse the central significance of the cell’s information storage and replication processes, even though the role of DNA and the genetic code was yet to be discovered.. (shrink)

One of the more recalcitrant issues in the philosophy of time concerns the question of temporal asymmetry. Some theorists, many of them, like Einstein, physicists, believe that time is fundamentally reversible. According to this view, the physical universe is indifferent to the direction of time; consequently, something like an arrow of time is held to be a human subjective imposition on an otherwise temporally isotropic world. Another position, held by Alfred North Whitehead and contemporary process philosophers, maintains that temporal asymmetry (...) is a primitive condition of the universe, and that therefore even the most basic physical processes, such as those occurring at the subatomic level, display a distinct temporal direction. Finally, the philosopher of time J.T. Fraser (1978) claims that temporal asymmetry is an emergent feature of the universe, appearing for the first time with biogenesis. According to Fraser, with the emergence of life comes a present, or “now”, a temporal dimension whose absence in more primitive levels of cosmic evolution prohibits the attribution of an arrow of time to any pre-biotic entity. (shrink)

Physical contact between organelles are widespread, in part to facilitate the shuttling of protein and lipid cargoes for cellular homeostasis. How do protein‐protein and protein‐lipid interactions shape organelle subdomains that constitute contact sites? The endoplasmic reticulum (ER) forms extensive contacts with multiple organelles, including lipid droplets (LDs) that are central to cellular fat storage and mobilization. Here, we focus on ER‐LD contacts that are highlighted by the conserved protein seipin, which promotes LD biogenesis and expansion. Seipin is enriched in (...) ER tubules that form cage‐like structures around a subset of LDs. Such enrichment is strongly dependent on polyunsaturated and cyclopropane fatty acids. Based on these findings, we speculate on molecular events that lead to the formation of seipin‐positive peri‐LD cages in which protein movement is restricted. We hypothesize that asymmetric distribution of specific phospholipids distinguishes cage membrane tubules from the bulk ER. (shrink)

Information transmission from tumor cells to non‐tumor cells in the surrounding microenvironment via microvesicles is a more recently studied form of intercellular signaling that can have a marked impact on the tumor microenvironment. Tumor‐derived microvesicles (TMVs) are packed with information including signaling proteins and nucleic acids, and can be taken up by target cells, enabling paracrine signaling. While previous research has focused on how vesicles released from pathologic cells differ from normal cells, the heterogeneity that exists within the TMV population (...) itself is not fully characterized, and only beginning to be appreciated. In this review, we summarize current understanding of the biogenesis and roles of shed TMVs in the tumor microenvironment, and speculate on the consequences for tumor cell signaling in light of the hypothesis that there exists variance within the TMV population. The analysis of differential signaling upon cell‐TMV interactions provides insights into potential mechanisms of intercellular communication. (shrink)

Centrosomes are the main microtubule organizing centers in animal cells. In particular during embryogenesis, they ensure faithful spindle formation and proper cell divisions. As metazoan centrosomes are eliminated during oogenesis, they have to be reassembled upon fertilization. Most metazoans use the sperm centrioles as templates for new centrosome biogenesis while the egg's cytoplasm re-prepares all components for on-going centrosome duplication in rapidly dividing embryonic cells. We discuss our knowledge and the experimental challenges to analyze zygotic centrosome reformation, which requires (...) genetic experiments to enable scrutinizing respective male and female contributions. Male and female knockout animals and mRNA injection to mimic maternal expression of centrosomal proteins could point a way to the systematic molecular dissection of the process. The most recent data suggest that timely expression of centrosome components in oocytes is the key to zygotic centrosome reformation that uses male sperm as coordinators for de novo centrosome production. Centrosome reformation at fertilization is essential for metazoan development. It requires a complicated interplay of sperm centrioles and the cytoplasm of the oocyte, which has eliminated its centrioles during oogenesis. The male centrioles launch centrosome duplication using female centrosome proteins for the first metazoan cell divisions. (shrink)

Cellular processes are highly dependent on a dynamic proteome that undergoes structural and functional rearrangements to allow swift conversion between different cellular states. By inducing proteasomal degradation of inhibitory or stimulating factors, ubiquitylation is particularly well suited to trigger such transitions. One prominent example is the remodelling of the centrosome upon cell cycle exit, which is required for the formation of primary cilia – antenna‐like structures on the surface of most cells that act as integrative hubs for various extracellular signals. (...) Over the last decade, many reports on ubiquitin‐related events involved in the regulation of ciliogenesis have emerged. Very often, these processes are considered to be initiated ad hoc, that is, directly before its effect on cilia biogenesis becomes evident. While such a temporal restriction may hold true for the majority of events, there is evidence that some of them are initiated earlier during the cell cycle. Here, we provide an overview of ubiquitin‐dependent processes in ciliogenesis and discuss available data that indicate such an early onset of proteolytic regulation within preceding cell cycle stages. (shrink)

In this chapter we offer a critical analysis of organizational models about the process of origins of life and, thereby, a reflection about life itself (understood in a general, minimal sense). We begin by demarcating the idea of organization as an explanatory construct, linking it to the complex relationships and transformations that the material parts of (proto-)biological systems establish to maintain themselves under non-equilibrium dynamic conditions. The diverse ways in which this basic idea has been applied within the prebiotic field (...) are then reviewed in relative detail. We distinguish between “network” and “protocell” approaches, discussing their specific implications and explaining the greater relevance of the latter in the current state of affairs. Despite the key role that such organizational approaches play (and should keep playing) to advance on the problem of primordial biogenesis, the second half of our contribution is devoted to argue that they must be combined with other explanatory accounts, which go beyond the physiology of any single (proto-)organism. With that aim, we underline the fundamental differences between the autonomous, metabolic dynamics that individual (proto-)cells perform and the evolutionary and ecological dynamics that take place in a collective and trans-generational dimension. Apart from obvious gaps in the characteristic temporal and spatial scales involved, the corresponding causal and interactive regimes also reveal themselves as neatly distinct, what is reflected in the unpaired functional integration and the agent behavior displayed by biological individuals. Nevertheless, any living organism (and life in a wider, general sense) derives from the deep interweaving of those two phenomenological domains: namely, the “individual-metabolic” and the “collective-evolutionary” domains. At the end of the chapter, we propose the principle of dynamical decoupling as the core idea to develop a more comprehensive theoretical framework to understand how this intricate, causally asymmetric connection must be articulated during the actual process of biogenesis (as it happened here on Earth or anywhere else in the universe), so that life’s minimal complexity threshold is reached. (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)

It is now clear that two prominent nuclear domains, interchromatin granule clusters (IGCs) and Cajal bodies (CBs), contribute to the highly ordered organization of the extrachromosomal space of the cell nucleus. These functional domains represent structurally stable but highly dynamic nuclear organelles enriched in factors that are required for different nuclear activities, especially RNA biogenesis. IGCs are considered to be the main sites for storage, assembly, and/or recycling of the essential spliceosome components. CBs are involved in the biogenesis (...) of several classes of small RNPs as well as the modification of newly assembled small nuclear RNA. We have summarized data on the molecular composition, structure, and functional roles of IGCs and CBs in the nuclei of mammalian somatic cells and oocytes of some animals with a special focus on insects. We have focused on similarities and differences between the IGCs and CBs of oocytes and the well‐studied CBs and IGCs of cultured mammalian somatic cells. We have shown the heterogeneous character of oocyte IGCs and CBs, both in structure and molecular content. We have also demonstrated the unique capacity of oocytes to form close structural interactions between IGC and CB components. We proposed to consider these joint structures as integrated entities, sharing the features of both IGCs and CBs. (shrink)

PTEN‐induced kinase 1 (PINK1) is a Parkinson's disease gene that acts as a sensor for mitochondrial damage. Its best understood role involves phosphorylating ubiquitin and the E3 ligase Parkin (PRKN) to trigger a ubiquitylation cascade that results in selective clearance of damaged mitochondria through mitophagy. Here we focus on other physiological roles of PINK1. Some of these also lie upstream of Parkin but others represent autonomous functions, for which alternative substrates have been identified. We argue that PINK1 orchestrates a multi‐arm (...) response to mitochondrial damage that impacts on mitochondrial architecture and biogenesis, calcium handling, transcription and translation. We further discuss a role for PINK1 in immune signalling co‐ordinated at mitochondria and consider the significance of a freely diffusible cleavage product, that is constitutively generated and degraded under basal conditions. (shrink)

Transfer RNAs (tRNAs) represent the most abundant class of RNA molecules in the cell and are key players during protein synthesis and cellular homeostasis. Aberrations in the extensive tRNA biogenesis pathways lead to severe neurological disorders in humans. Mutations in the tRNA splicing endonuclease (TSEN) and its associated RNA kinase cleavage factor polyribonucleotide kinase subunit 1 (CLP1) cause pontocerebellar hypoplasia (PCH), a heterogeneous group of neurodegenerative disorders, that manifest as underdevelopment of specific brain regions typically accompanied by microcephaly, profound (...) motor impairments, and child mortality. Recently, we demonstrated that mutations leading to specific PCH subtypes destabilize TSEN in vitro and cause imbalances of immature to mature tRNA ratios in patient‐derived cells. However, how tRNA processing defects translate to disease on a systems level has not been understood. Recent findings suggested that other cellular processes may be affected by mutations in TSEN/CLP1 and obscure the molecular mechanisms of PCH emergence. Here, we review PCH disease models linked to the TSEN/CLP1 machinery and discuss future directions to study neuropathogenesis. (shrink)

The Endosomal Sorting Complexes Required for Transport (ESCRTs) drive membrane remodeling in a variety of cellular processes that include the formation of endosomal intralumenal vesicles (ILVs) during multivesicular body (MVB) biogenesis. During MVB sorting, ESCRTs recognize ubiquitin (Ub) attached to membrane protein cargo and execute ILV formation by controlling the activities of ESCRT‐III polymers regulated by the AAA‐ATPase Vps4. Exactly how these events are coordinated to ensure proper cargo loading into ILVs remains unclear. Here we discuss recent work documenting (...) the ability of Bro1, an ESCRT‐associated Ub‐binding protein, to coordinate ESCRT‐III and Vps4‐dependent ILV biogenesis with upstream events such as cargo recognition. (shrink)

The problem of causality is presented in the context of the research devoted to biogenesis. The significant works concerning the philosophy of biogenesis and scientific theories of abioge­nesis have been reviewed. Special attention is paid to: (i) the role of the non-equilibrium thermo­dynamics and quantum mechanics in the explaining of causal relations involved the origins of life, (ii) the need of constructing of a quantum logic of life. It is suggested that the causal con­nection is established by an (...) information channel between a cause and its result. (shrink)

Autophagy, an essential cellular process for maintaining cellular homeostasis and eliminating harmful cytoplasmic objects, involves the de novo formation of double‐membraned autophagosomes that engulf and degrade cellular debris, protein aggregates, damaged organelles, and pathogens. Central to this process is the phagophore, which forms from donor membranes rich in lipids synthesized at various cellular sites, including the endoplasmic reticulum (ER), which has emerged as a primary source. The ER‐associated omegasomes, characterized by their distinctive omega‐shaped structure and accumulation of phosphatidylinositol 3‐phosphate (PI3P), (...) play a pivotal role in autophagosome formation. Omegasomes are thought to serve as platforms for phagophore assembly by recruiting essential proteins such as DFCP1/ZFYVE1 and facilitating lipid transfer to expand the phagophore. Despite the critical importance of phagophore biogenesis, many aspects remain poorly understood, particularly the complete range of proteins involved in omegasome dynamics, and the detailed mechanisms of lipid transfer and membrane contact site formation. (shrink)

This paper compares two approaches that attempt to explain the origin of life, or biogenesis. The more established approach is one based on chemical principles, whereas a new, yet not widely known approach begins from a physical perspective. According to the first approach, life would have begun with—often organic—compounds. After having developed to a certain level of complexity and mutual dependence within a non-compartmentalised organic soup, they would have assembled into a functioning cell. In contrast, the second, physical type (...) of approach has life developing within tiny compartments from the beginning. It emphasises the importance of redox reactions between inorganic elements and compounds found on two sides of a compartmental boundary. Without this boundary, “ life ” would not have begun, nor have been maintained; this boundary—and the complex cell membrane that evolved from it—forms the essence of life. (shrink)

Astrobiologists are aware that extraterrestrial life might differ from known life, and considerable thought has been given to possible signatures associated with weird forms of life on other planets. So far, however, very little attention has been paid to the possibility that our own planet might also host communities of weird life. If life arises readily in Earth-like conditions, as many astrobiologists contend, then it may well have formed many times on Earth itself, which raises the question whether one or (...) more shadow biospheres have existed in the past or still exist today. In this paper, we discuss possible signatures of weird life and outline some simple strategies for seeking evidence of a shadow biosphere. Key Words: Weird life—Multiple origins of life—Biogenesis—Biomarkers—Extremophiles—Alternative biochemistry. Astrobiology 9, 241–249. (shrink)

The cartwheel is a striking structure critical for building the centriole, a microtubule-based organelle fundamental for organizing centrosomes, cilia, and flagella. Over the last 50 years, the cartwheel has been described in many systems using electron microscopy, but the molecular nature of its constituent building blocks and their assembly mechanisms have long remained mysterious. Here, we review discoveries that led to the current understanding of cartwheel structure, assembly, and function. We focus on the key role of SAS-6 protein self-organization, both (...) for building the signature ring-like structure with hub and spokes, as well as for their vertical stacking. The resemblance of assembly intermediates in vitro and in vivo leads us to propose a novel registration step in cartwheel biogenesis, whereby stacked SAS-6-containing rings are put in register through interactions with peripheral elements anchored to microtubules. We conclude by evoking some avenues for further uncovering cartwheel and centriole assembly mechanisms. The cartwheel is crucial for centriole assembly. Despite this fundamental role, cartwheel structure and assembly mechanisms remain unclear for a long time. Here we review five decades of research that led to our current understanding of these questions, highlighting the central role of the SAS-6 protein family. (shrink)