Organelles, defined as intracellular membrane-bound structures in eukaryotic cells, were described from the early days of light microscopy and the development of cell theory in the 19^th century. During the 20^th century, electron microscopy and subcellular fractionation enabled the discovery of additional organelles and, together with radiolabelling, allowed the first modern experiments on their biogenesis. Over the past 30 years, the development of cell-free systems and the use of yeast genetics have together established the major pathways of delivery of newly synthesised proteins to organelles and the vesicular traffic system used to transfer cargo between organelles in the secretory and endocytic pathways. Mechanisms of protein sorting, retrieval and retention have been described and give each organelle its characteristic composition. Insights have been gained into the mechanisms by which complex organelle morphology can be established. Organelle biogenesis includes the process of organelle inheritance by which organelles are divided between daughter cells during mitosis. Two inheritance strategies have been described, stochastic and ordered, which are not mutually exclusive. Among the major challenges of the future are the need to understand the role of self-organization in ensuring structural stability and the mechanisms by which a cell senses the status of its organelles and regulates their biogenesis.

Introduction

Today, cell biologists are almost overwhelmed by molecular detail about organelle composition, structure, function and biogenesis. Nevertheless during the molecular era, which has encompassed the past half century, a conceptual framework has developed to explain processes such as protein sorting, membrane traffic and organelle biogenesis. In this chapter we review this development, together with earlier work that established the existence of organelles and traffic to them. Necessarily, we cannot include specific detail about all organelles and we have concentrated, for the most part, on those found on the secretory and endocytic pathways.¹ We begin with some definitions.

Definitions

Organelles are defined as intracellular membrane-bound structures in eukaryotic cells, usually specialized for a particular function.² While many organelles are morphologically similar and perform essentially the same function in all eukaryotic cells, some are specialized and occur only in particular cell types. Among the former are the nucleus, mitochondria and or- ganelles in the secretory and endocytic pathways including the endoplasmic reticulum, Golgi complex, endosomes and lysosomes (vacuoles in yeast), whereas the latter include chloroplasts restricted to the plant kingdom. In mammalian cells there has been much study of cell type-specific specialist organelles and their relationship to common organelles. Many, if not all, of these are specialized structures in the secretory and endocytic pathways and include, for example, regulated secretory granules in neuroendocrine cells³ and melanosomes,⁴ which are clearly lysosome-like, in skin melanocytes.

Organelle biogenesis is the process by which new organelles are made. In a few cases, notably mitochondria and chloroplasts, some organelle proteins are encoded by the organelle's own genome. However, the amount of DNA in such organelles can encode only a very small number of the many proteins required.⁵ In practice, the study of organelle biogenesis includes the mechanisms by which proteins and lipids, newly synthesized elsewhere in the cell, are delivered to organelles and the process by which organelles are divided between daughter cells during mitosis. In general it is thought that new organelles are derived by proliferation of preexisting organelles.⁶ However, for some organelles on the secretory and endocytic pathways, e.g., the Golgi complex (see below), the extent to which they can be made de novo by a cell without a preexisting organelle or template remains a subject of controversy.⁷

The History of Organelle Recognition

Protein Synthesis and Targeting

Although Palade had established that newly synthesised secretory proteins crossed into the lumen of the endoplasmic reticulum, it required the experiments of Blobel and his colleagues to establish that this sorting and targeting event was mediated by a sequence motif within the primary sequence of the secretory protein, which was named the signal sequence.⁴⁵ To test the predictions of the signal hypothesis, first announced in 1971, Blobel developed a cell-free system in which protein translation and protein translocation across microsomal membrane vesicles could be measured. This cell-free system was a powerful forerunner of many others established elsewhere which faithfully recapitulated individual steps in organelle biogenesis pathways. The signal hypothesis also led directly to the concept that specific sequences within a protein could direct its targeting to a particular organelle. Thus, different consensus sequences have since been recognized as targeting motifs for import into mitochondria,⁴⁶ chloroplasts,⁴⁷ peroxisomes,⁴⁸ nuclei⁴⁹ and for the targeting of membrane proteins on secretory and endocytic pathways. Subsequent to the discovery of consensus sequences targeting proteins to particular organelles, there has been much work over the past 20 years identifying the protein machinery required for transport into such organelles, leading to an extensive understanding of transport to the mitochondrial matrix,⁴⁶ inner membrane,⁵⁰ outer membrane,⁵¹ into chloroplasts,⁵² into peroxisomes⁵³ and through nuclear pores.⁵⁴. In addition to amino acid sequence motifs, secondary modifications have also been recognized as targeting motifs, for example mannose 6-phosphate to target acid hydrolases from the Golgi complex to lysosomes⁵⁵ and both glycosylation and glycosylphosphatidylinositol membrane anchors to target proteins to the apical surface of polarized epithelial cells.⁵⁶

A further bequest of the signal hypothesis was that testing it provided support for the idea that in evolution the eukaryotic endoplasmic reticulum arose by invagination of the prokaryotic plasma membrane since signal sequences addressed to the eukaryotic endoplasmic reticulum function in translocation across the prokaryotic plasma membrane and signal sequences for bacterial secretory proteins function in translocation across the eukaryotic endoplasmic reticulum.⁵⁷ In contrast, it had earlier been suggested that uptake of a prokaryotic progenitor cell(s) was the evolutionary origin of mitochondria and chloroplasts,⁵⁸ a hypothesis largely supported by the results of subsequent genome analysis which were consistent with the origin of the mitochondrion being an endosymbiotic α-proteobacterium.⁵⁹

Cell-Free Systems and Yeast Genetics

Vesicular traffic is now accepted as the central mechanism by which proteins are transported between donor and acceptor compartments on the secretory and endocytic pathways⁶⁰ (Fig. 1). The discovery of clathrin by Pearse in the 1970s⁶¹ provided the first coat component of vesicles involved in membrane traffic. However, it was during the 1980s that elucidation of the molecular machinery of vesicular traffic started in earnest with the reconstitution of individual traffic steps in cell-free systems from animal cells⁶² and the isolation of secretory mutants in yeast.⁶³ Probably the most informative of these early cell-free systems was one in which vesicular traffic between Golgi cisternae was reconstituted by incubating Golgi membranes with cytosol and ATP.⁶⁴ In this system a population of Golgi membranes derived from cells lacking N-acetylglucosamine transferase but containing the G protein of vesicular stomatatis virus (VSV) was incubated with an population of Golgi membranes from wild type cells. Vesicular traffic resulted in addition of radioactive N-acetylglucosamine to the VSV-G as a result of the activity of the transferase in the wild type Golgi membranes. This assay led directly to the discovery of COPI (coat protein I) coated vesicles⁶⁵ and the discovery of components of the general cytosolic fusion machinery required for vesicle fusion with acceptor membranes throughout the secretory and endocytic pathways.⁶⁶ Subsequently, using the same principles of incubating organelle membrane fractions with cytosol and ATP, many membrane traffic steps were reconstituted in cell-free systems. Similarly, cell-free assays were established to look at the breakdown and reformation of organelles during cell division.

Figure 1

Mechanisms for organelle biogenesis in the secretory and endocytic pathways. A) Vesicular traffic. A coated vesicle buds from a donor organelle, loses its coat and fuses with an acceptor organelle. The coat made up of cytosolic proteins (denoted by black (more...)

The isolation of secretion (sec) mutants in the budding yeast Saccharomyces cerevisiae⁶³ provided a powerful approach to identify proteins required for traffic through the secretory pathway and to study their function. Throughout the 1980s and 1990s many proteins necessary for membrane traffic on the secretory pathway were identified almost at the same time, either by fractionating mammalian cytosol or through characterization of yeast mutants. These studies established the similarities of membrane traffic pathways at the molecular level in all eukaryotes.⁶⁰ The genetic screens in yeast which allowed isolation of the original temperature-sensitive and other sec mutants were followed by many others, for example those identifying genes affected in vacuolar protein sorting (vps ) mutants^67,68 and those identifying genes involved in autophagy.⁶⁹ These latter screens led directly to our current understanding of the molecular mechanisms of biogenesis of the vacuole, of its mammalian equivalent the lysosome⁷⁰ and of autophagosomes in both yeast and mammalian cells.^69,70 In recent years, the development of cell-free systems to study homotypic yeast vacuole fusion, together with yeast genetics,⁷¹ have led to a massive expansion in our understanding of what is effectively a multi-protein machine required to achieve vacuole membrane fusion, a process essential to vacuole biogenesis in the daughter bud of a dividing yeast.

Organization into Complex Structures

Organelle biogenesis is not simply a question of delivering newly synthesized proteins and lipids to a specific intracellular site but may also require the establishment of a complex architecture. A dramatic example of this is seen in the case of the Golgi complex where it is clear that the observed morphology in part reflects the interaction of the structure with the cytoskeleton via appropriate motor proteins¹⁰³ and in part the function of matrix proteins in the organization of the cisternae.^104,105 A further complication, particularly for organelles on the secretory and endocytic pathways, is the requirement to maintain morphological form and associated functional integrity despite the large volume of through traffic of both proteins and lipids. In the case of the Golgi complex, there has long been a debate about how secreted proteins pass through it.¹⁰⁶ The work of Rothman and colleagues described above on reconstituting traffic through the Golgi complex in a cell-free system suggested anterograde vesicular traffic between the Golgi cisternae. However, electron microscopy studies of large macromolecules, including algal scales and collagen aggregates favoured a maturation model with new cisternae forming on the cis-side and mature ones fragmenting from the trans-side. The cisternal maturation model has been refined to encompass data on retrograde vesicular traffic in COPI coated vesicles such that the present consensus is that most, if not all, anterograde movement through the Golgi complex is the result of cisternal progression with retrograde vesicular traffic ensuring that the polarized distribution of Golgi enzymes in the cisternal stack is maintained (Fig. 1).¹⁰⁷ A recent three dimensional reconstruction of the Golgi complex from data obtained by high voltage electron microscopy has suggested that tubular and vesicular structures can bud at every level of the Golgi stack.¹⁰⁸ Structurally, using conventional electron microscopy techniques, and functionally, the trans-Golgi network can be distinguished from the cisternal stack and is defined as the site for sorting to different post-Golgi destinations.¹⁰⁹ Both clathrin-coated vesicles and noncoated tubular structures appear to bud from the trans-Golgi network. Experiments in which secreted proteins tagged with green fluorescent protein have been imaged as they leave the Golgi complex in living cells have shown that large tubular carriers are particularly important for constitutive traffic to the cell surface.¹¹⁰ In many neuroendocrine cell types, regulated secretory granules are also formed at the trans-Golgi network. Despite the biogenesis of such organelles being amongst the first to be studied by radiolabelling pulse-chase techniques (see above), the mechanisms by which proteins are sorted into these granules remain unclear, with “sorting for entry” and “sorting by retention” models still the subject of much debate.³

In the endocytic pathway, the biogenesis of individual organelles has been less well studied with the exception of lysosomes and the yeast vacuole.¹¹¹¹¹³ This has partly been due to the pleiomorphic morphology of endosomes, partly to the difficulty of identifying marker proteins that, at steady state, are mainly localized in endosomes and partly because the molecular mechanisms of membrane traffic through the pathway have only started to be understood in the last few years. As in the secretory pathway, vesicular traffic between individual organelles does not explain all steps in the pathway. Clathrin-coated vesicles budding from the plasma membrane comprise a very important, but not sole, mechanism of delivery from the plasma membrane to early endosomes (defined historically as the first endosomal compartment to be entered by endocytosed ligands). Traffic from early to late endosomes, found deeper within the cell, has been studied extensively and is mediated by large endocytic carrier vesicles which some regard as matured early endosomes.^114,115 Delivery from late endosomes to lysosomes involves “kiss and run” and direct fusion between the two organelles. Such fusion is SNARE-mediated and results in a hybrid organelle from which lysosomes are reformed. In addition to heterotypic fusion between late endosomes and lysosomes, the endocytic pathway is characterized by the occurrence of homotypic fusions between early endosomes and between late endosomes. These homotypic fusion events are also SNARE-mediated^116,117 and allow continuous remodelling of these organelles. Organelles in the late endocytic pathway are characterised by the presence of numerous internal vesicles, leading to the alternative description of late endosomes as multivesicular bodies. Some cell surface receptors are sorted into such vesicles after internalization from the plasma membrane and prior to degradation. Recently, insights have been gained into the molecular mechanisms by which proteins are sorted into these vesicles, which have a different lipid composition from the limiting membrane of the organelle. Such mechanisms include partitioning into lipid microdomains, dependent on the composition of trans-membrane domains, and ubiquitination of cytoplamic tail domains followed by recognition of the ubiquinated domain by protein complexes involved in inward vesiculation.^118,119

Organelle Inheritance

Organelle biogenesis is closely linked to organelle inheritance in cell division. During the cell cycle, each organelle must double in size, divide and be delivered appropriately to the daughter cells. Historically, the inheritance of organelles was recognised as occurring over the same period of the late 19^th and early 20^th centuries as the basic mechanics of mitosis were being described.^13,120122 In summarizing a large amount of earlier work, Warren and Wickner¹²⁰ categorized two organelle inheritance strategies that have been described. The first is stochastic, relying on the presence of multiple copies of an organelle randomly distributed throughout the cytoplasm and the second is ordered, often, but not always, using the mitotic spindle as a means of partitioning (Fig. 2). The morphology of many organelles may differ in different cell types, which itself may be related to the use of one or other of these strategies to a greater or lesser extent. Mitochondria, for example are, in many cells, multiple copies of small bean shaped structures, but in the budding yeast S. cerevisiae form an extensive tubular reticulum beneath the plasma membrane which partitions in an ordered way into the bud. The steady-state morphology of mitochondria which continuously grow, divide and fuse throughout the cell cycle is itself largely determined by the frequency of fission events and fusion.¹²³ It should be noted that growth and division of mitochondria also requires coordination of these processes for the inner and outer membranes. In contrast to mitochondria, the endoplasmic reticulum is always a single copy organelle, albeit a dynamic reticulum. This breaks down into tubular vesicular elements during cell division to a variable extent. It often fragments little, thus segregation of equal amounts into daughter cells during mitosis may rely mainly on the uniform and extensive distribution of the endoplasmic reticulum network throughout the cytoplasm of the mother cell. In S. cerevisiae the endoplasmic reticulum becomes anchored at the bud tip pulling the network into the bud as it enlarges.¹²⁴ Whereas the bulk of the endoplasmic reticulum often does not fragment during mitosis, inheritance of the nuclear envelope, the outer membrane of which is continuous with the endoplasmic reticulum, is more complex since it has to break down during mitosis of animal cells to allow separation of the chromatids. At the end of mitosis the nuclear envelope rapidly reassembles around daughter chromosomes. During the 1980's, nuclear envelope breakdown in animal cells was shown to involve depolymerisation of the lamina underlying the membrane, fragmentation of the membrane and dissassembly of nuclear pore complexes.¹²⁵ This was accompanied by reversible phosphorylation of many nuclear envelope proteins thought to lead to the formation of a discrete population of vesicles which could fuse at the end of mitosis to reform the envelope. Using Xenopus oocytes, which contain many nuclear components stored for use in early development, it was observed that injection of bacteriophage lambda DNA or its addition to cell-free extracts was sufficient to trigger nuclear assembly.¹²⁶ The availability of this cell-free system enabled study, at the molecular level, of the pathway of nuclear assembly, including nuclear envelope vesicle fusion.¹²⁷ Recently, it has been suggested that the nuclear envelope does not have to vesiculate completely during mitosis, but that phosphorylation may allow redistribution of nuclear envelope membrane proteins back into the endoplasmic reticulum.¹²⁸ The lack of requirement for membrane vesiculation has raised the question of how the nuclear envelope ruptures, resolved by recent evidence that it is literally torn apart by motor protein attachment and movement along microtubules. ¹²⁸

Figure 2

Mechanisms for organelle inheritance during mitosis. In the “stochastic inheritance” model (solid arrows), an organelle, shown here as an anastomosed, reticular network with all the membrane having a common composition, vesiculates to (more...)

Perhaps the greatest recent controversy concerning organelle inheritance relates to how the Golgi complex is divided between daughter cells at mitosis.⁷ Two models have been proposed to explain this. In the first, proposed by Warren, the Golgi complex breaks down into vesicle clusters and shed vesicles which are distributed stochastically between the daughter cells where they reassemble in telophase.¹²⁹ Cell-free assays have led to the identification of some of the molecular machinery for disassembly and reassembly.¹³⁰ In the second model, proposed by Lippincott-Schwartz, endoplasmic reticulum is the partioning unit, with the Golgi complex merging with the endoplasmic reticulum during prometaphase and emerging from it during telophase.¹³¹ A key observation in developing this second model was that inhibition of traffic from the endoplasmic reticulum to the Golgi complex results in disintegration of the latter. Some of the discrepancies between the two models may be resolved by data from Warren's group who have shown that whilst Golgi membrane enzymes may, to a greater or lesser extent, redistribute to the endoplasmic reticulum during mitosis, matrix proteins do not, thus allowing the disassembled matrix to become the partitioning units on which the Golgi complex is reassembled after mitosis.^132,133 A further twist has come from the study of the protozoan Toxoplasma gondii which has a single Golgi that divides as a result of lateral cisternal growth followed by medial fission.¹³⁴ Even in mammalian cells, Golgi fragmentation-dispersion may not be obligatory for equal partitioning. Kondo and colleagues recently found that prevention of Golgi dissassembly, by microinjection of a nonphosphorylated mutant form of a soluble protein required for this process, had no effect on equal partitioning of the Golgi to daughter cells.¹³⁵

Challenges

It is now clear that intracellular organelles are very dynamic structures, yet at steady state they exhibit characteristic morphology and architecture that are easily observed by microscopy. Recently Misteli¹³³ has suggested that the generation of an overall stable configuration in such dynamic structures is consistent with organelle morphology being determined by self-organization. This is defined as “the capacity of a macromolecular complex or organelle to determine its own structure based on the functional interaction of its components”. Self-organization will ensure structural stability without loss of plasticity. Self-organization is an interesting concept, but how organelles self-organize is unclear. What is certain is that future investigations will lead us to a better understanding of the molecular machinery of organelle biogenesis and inheritance. Such investigations are likely to address a number of questions to which we have few answers at present. These include the role of lipids, in particular lipid-protein interactions in microdomains, in determining morphology and the regulation of the size, shape and number of organelles in cells.

Acknowledgements

We thank the Medical Research Council and the Wellcome Trust for supporting our experimental work on lysosome biogenesis and post-Golgi membrane traffic pathways.

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