Guyton & Hall 14th ed Chapter 2 PDF

CHAPTER 2 UNIT I...

CHAPTER 2 UNIT I The Cell and Its Functions Each of the trillions of cells in a human being is a living 20% of the cell mass. These proteins can be divided into structure that can survive for months or years, provided two types, structural proteins and functional proteins. its surrounding fluids contain appropriate nutrients. Cells Structural proteins are present in the cell mainly in the are the building blocks of the body, providing structure form of long filaments that are polymers of many indi- for the body’s tissues and organs, ingesting nutrients and vidual protein molecules. A prominent use of such intra- converting them to energy, and performing specialized cellular filaments is to form microtubules, which provide functions. Cells also contain the body’s hereditary code, the cytoskeletons of cellular organelles such as cilia, nerve which controls the substances synthesized by the cells axons, the mitotic spindles of cells undergoing mitosis, and permits them to make copies of themselves. and a tangled mass of thin filamentous tubules that hold the parts of the cytoplasm and nucleoplasm together in their respective compartments. Fibrillar proteins are ORGANIZATION OF THE CELL found outside the cell, especially in the collagen and elas- A schematic drawing of a typical cell, as seen by the light tin fibers of connective tissue, and elsewhere, such as in microscope, is shown in Figure 2-1. Its two major parts blood vessel walls, tendons, and ligaments. are the nucleus and the cytoplasm. The nucleus is sepa- The functional proteins are usually composed of com- rated from the cytoplasm by a nuclear membrane, and the binations of a few molecules in tubular-globular form. cytoplasm is separated from the surrounding fluids by a These proteins are mainly the enzymes of the cell and, in cell membrane, also called the plasma membrane. contrast to the fibrillar proteins, are often mobile in the The different substances that make up the cell are cell fluid. Also, many of them are adherent to membra- collectively called protoplasm. Protoplasm is composed nous structures inside the cell and catalyze specific intra- mainly of five basic substances—water, electrolytes, pro- cellular chemical reactions. For example, the chemical teins, lipids, and carbohydrates. reactions that split glucose into its component parts and then combine these with oxygen to form carbon diox- Water. Most cells, except for fat cells, are comprised ide and water while simultaneously providing energy for mainly of water in a concentration of 70% to 85%. Many cellular function are all catalyzed by a series of protein cellular chemicals are dissolved in the water. Others are enzymes.␣ suspended in the water as solid particulates. Chemical re- actions take place among the dissolved chemicals or at the Lipids. Lipids are several types of substances that are surfaces of the suspended particles or membranes.␣ grouped together because of their common property of being soluble in fat solvents. Especially important lipids Ions. Important ions in the cell include potassium, magne- sium, phosphate, sulfate, bicarbonate, and smaller quanti- ties of sodium, chloride, and calcium. These ions are all Cell discussed in Chapter 4, which considers the interrelations membrane between the intracellular and extracellular fluids. The ions provide inorganic chemicals for cellular reac- Cytoplasm tions and are necessary for the operation of some cellular Nucleolus control mechanisms. For example, ions acting at the cell Nucleoplasm Nuclear membrane are required for the transmission of electro- membrane Nucleus chemical impulses in nerve and muscle fibers.␣ Proteins. After water, the most abundant substances in most cells are proteins, which normally constitute 10% to Figure 2-1. Illustration of cell structures visible with a light microscope. 13 UNIT I Introduction to Physiology: The Cell and General Physiology Chromosomes and DNA Centrioles Secretory granule Golgi apparatus Microtubules Nuclear membrane Cell membrane Nucleolus Glycogen Ribosomes Lysosome Mitochondrion Rough (granular) Smooth (agranular) Microfilaments endoplasmic endoplasmic reticulum reticulum Figure 2-2. Reconstruction of a typical cell, showing the internal organelles in the cytoplasm and nucleus. are phospholipids and cholesterol, which together consti- that it is readily available to the cell. Also, a small amount tute only about 2% of the total cell mass. Phospholipids of carbohydrate is stored in cells as glycogen, an insoluble and cholesterol are mainly insoluble in water and there- polymer of glucose that can be depolymerized and used fore are used to form the cell membrane and intracellular rapidly to supply the cell’s energy needs.␣ membrane barriers that separate the different cell com- partments. CELL STRUCTURE In addition to phospholipids and cholesterol, some cells contain large quantities of triglycerides, also called The cell contains highly organized physical structures neutral fats. In fat cells (adipocytes), triglycerides often called intracellular organelles, which are critical for cell account for as much as 95% of the cell mass. The fat stored function. For example, without one of the organelles, the in these cells represents the body’s main storehouse of mitochondria, more than 95% of the cell’s energy release energy-giving nutrients that can later be used to provide from nutrients would cease immediately. The most energy wherever it is needed in the body.␣ important organelles and other structures of the cell are shown in Figure 2-2. Carbohydrates. Carbohydrates play a major role in cell nutrition and, as parts of glycoprotein molecules, have MEMBRANOUS STRUCTURES OF THE CELL structural functions. Most human cells do not maintain large stores of carbohydrates; the amount usually averages Most organelles of the cell are covered by membranes only about 1% of their total mass but increases to as much composed primarily of lipids and proteins. These mem- as 3% in muscle cells and, occasionally, to 6% in liver cells. branes include the cell membrane, nuclear membrane, However, carbohydrate in the form of dissolved glucose membrane of the endoplasmic reticulum, and membranes is always present in the surrounding extracellular fluid so of the mitochondria, lysosomes, and Golgi apparatus. 14  Chapter 2 The Cell and Its Functions Carbohydrate Extracellular fluid UNIT I Integral protein Lipid bilayer Peripheral protein Intracellular fluid Cytoplasm Integral protein Figure 2-3. Structure of the cell membrane showing that it is composed mainly of a lipid bilayer of phospholipid molecules, but with large numbers of protein molecules protruding through the layer. Also, carbohydrate moieties are attached to the protein molecules on the outside of the membrane and to additional protein molecules on the inside. The lipids in membranes provide a barrier that continuous over the entire cell surface. Interspersed in impedes movement of water and water-soluble sub- this lipid film are large globular proteins. stances from one cell compartment to another because The basic lipid bilayer is composed of three main types water is not soluble in lipids. However, protein mole- of lipids—phospholipids, sphingolipids, and cholesterol. cules often penetrate all the way through membranes, Phospholipids are the most abundant cell membrane thus providing specialized pathways, often organized lipids. One end of each phospholipid molecule is hydro- into actual pores, for passage of specific substances philic and soluble in water. The other end is hydropho- through membranes. Also, many other membrane bic and soluble only in fats. The phosphate end of the proteins are enzymes, which catalyze a multitude of phospholipid is hydrophilic, and the fatty acid portion is different chemical reactions, discussed here and in sub- hydrophobic. sequent chapters. Because the hydrophobic portions of the phospholipid molecules are repelled by water but are mutually attracted Cell Membrane to one another, they have a natural tendency to attach to The cell membrane (also called the plasma membrane) one another in the middle of the membrane, as shown in envelops the cell and is a thin, pliable, elastic structure Figure 2-3. The hydrophilic phosphate portions then con- only 7.5 to 10 nanometers thick. It is composed almost stitute the two surfaces of the complete cell membrane, in entirely of proteins and lipids. The approximate composi- contact with intracellular water on the inside of the mem- tion is 55% proteins, 25% phospholipids, 13% cholesterol, brane and extracellular water on the outside surface. 4% other lipids, and 3% carbohydrates. The lipid layer in the middle of the membrane is impermeable to the usual water-soluble substances, such The Cell Membrane Lipid Barrier Impedes Penetra- as ions, glucose, and urea. Conversely, fat-soluble sub- tion by Water-Soluble Substances. Figure 2-3 shows stances, such as oxygen, carbon dioxide, and alcohol, can the structure of the cell membrane. Its basic structure penetrate this portion of the membrane with ease. is a lipid bilayer, which is a thin, double-layered film Sphingolipids, derived from the amino alcohol sphin- of lipids—each layer only one molecule thick—that is gosine, also have hydrophobic and hydrophilic groups and 15  UNIT I Introduction to Physiology: The Cell and General Physiology are present in small amounts in the cell membranes, espe- these molecules almost invariably protrude to the outside cially nerve cells. Complex sphingolipids in cell mem- of the cell, dangling outward from the cell surface. Many branes are thought to serve several functions, including other carbohydrate compounds, called proteoglycans— protection from harmful environmental factors, signal which are mainly carbohydrates bound to small protein transmission, and adhesion sites for extracellular proteins. cores—are loosely attached to the outer surface of the cell Cholesterol molecules in membranes are also lipids as well. Thus, the entire outside surface of the cell often because their steroid nuclei are highly fat-soluble. These has a loose carbohydrate coat called the glycocalyx. molecules, in a sense, are dissolved in the bilayer of the The carbohydrate moieties attached to the outer sur- membrane. They mainly help determine the degree of face of the cell have several important functions: permeability (or impermeability) of the bilayer to water- 1. Many of them have a negative electrical charge, soluble constituents of body fluids. Cholesterol controls which gives most cells an overall negative surface much of the fluidity of the membrane as well.␣ charge that repels other negatively charged objects. 2. The glycocalyx of some cells attaches to the glycoca- Integral and Peripheral Cell Membrane Proteins. lyx of other cells, thus attaching cells to one another. Figure 2-3 also shows globular masses floating in the 3. Many of the carbohydrates act as receptors for bind- lipid bilayer. These membrane proteins are mainly glyco- ing hormones, such as insulin. When bound, this proteins. There are two types of cell membrane proteins, combination activates attached internal proteins that integral proteins, which protrude all the way through in turn activate a cascade of intracellular enzymes. the membrane, and peripheral proteins, which are 4. Some carbohydrate moieties enter into immune re- attached only to one surface of the membrane and do actions, as discussed in Chapter 35.␣ not penetrate all the way through. Many of the integral proteins provide structural chan- CYTOPLASM AND ITS ORGANELLES nels (or pores) through which water molecules and water- soluble substances, especially ions, can diffuse between The cytoplasm is filled with minute and large dispersed extracellular and intracellular fluids. These protein chan- particles and organelles. The jelly-like fluid portion of the nels also have selective properties that allow preferential cytoplasm in which the particles are dispersed is called diffusion of some substances over others. cytosol and contains mainly dissolved proteins, electro- p Other integral proteins act as carrier proteins for trans- lytes, and glucose. · maand/ porting substances that otherwise could not penetrate Dispersed in the cytoplasm are neutral fat globules, pore the lipid bilayer. Sometimes, these carrier proteins even glycogen granules, ribosomes, secretory vesicles, and five Asfire transport substances in the direction opposite to their especially important organelles—the endoplasmic reticu- transport · electrochemical gradients for diffusion, which is called lum, the Golgi apparatus, mitochondria, lysosomes, and active transport. Still others act as enzymes. peroxisomes. Receptors Integral membrane proteins can also serve as receptors Endoplasmic Reticulum commons · for water-soluble chemicals, such as peptide hormones, · that do not easily penetrate the cell membrane. Interac- Figure 2-2 shows the endoplasmic reticulum, a network intos tion of cell membrane receptors with specific ligands that of tubular structures called cisternae and flat vesicular bind to the receptor causes conformational changes in structures in the cytoplasm. This organelle helps pro- the receptor protein. This process, in turn, enzymatically cess molecules made by the cell and transports them to activates the intracellular part of the protein or induces their specific destinations inside or outside the cell. The interactions between the receptor and proteins in the tubules and vesicles interconnect. Also, their walls are cytoplasm that act as second messengers, relaying the sig- constructed of lipid bilayer membranes that contain large nal from the extracellular part of the receptor to the inte- amounts of proteins, similar to the cell membrane. The rior of the cell. In this way, integral proteins spanning the total surface area of this structure in some cells—the liver cell membrane provide a means of conveying information cells, for example—can be as much as 30 to 40 times the about the environment to the cell interior. cell membrane area. Peripheral protein molecules are often attached to The detailed structure of a small portion of endoplas- integral proteins. These peripheral proteins function mic reticulum is shown in Figure 2-4. The space inside almost entirely as enzymes or as controllers of transport the tubules and vesicles is filled with endoplasmic matrix, of substances through cell membrane pores.␣ a watery medium that is different from fluid in the cytosol outside the endoplasmic reticulum. Electron micrographs Membrane Carbohydrates—The Cell “Glycocalyx.” show that the space inside the endoplasmic reticulum is Membrane carbohydrates occur almost invariably in com- connected with the space between the two membrane bination with proteins or lipids in the form of glycopro- surfaces of the nuclear membrane. teins or glycolipids. In fact, most of the integral proteins Substances formed in some parts of the cell enter the are glycoproteins, and about one-tenth of the membrane space of the endoplasmic reticulum and are then directed lipid molecules are glycolipids. The glyco- portions of to other parts of the cell. Also, the vast surface area of this 16  Chapter 2 The Cell and Its Functions Ribosome Golgi vesicles Matrix Golgi UNIT I apparatus ER vesicles Endoplasmic reticulum Rough (granular) endoplasmic reticulum Smooth (agranular) endoplasmic Figure 2-5. A typical Golgi apparatus and its relationship to the reticulum endoplasmic reticulum (ER) and the nucleus. Figure 2-4. Structure of the endoplasmic reticulum. vesicles are transported from the endoplasmic reticulum reticulum and the multiple enzyme systems attached to to the Golgi apparatus. The transported substances are its membranes provide the mechanisms for a major share then processed in the Golgi apparatus to form lysosomes, of the cell’s metabolic functions. secretory vesicles, and other cytoplasmic components (discussed later in this chapter).␣ Ribosomes and the Rough (Granular) Endoplasmic Reticulum. Attached to the outer surfaces of many parts Lysosomes of the endoplasmic reticulum are large numbers of minute Lysosomes, shown in Figure 2-2, are vesicular organ- granular particles called ribosomes. Where these particles elles that form by breaking off from the Golgi appara- are present, the reticulum is called the rough (granular) tus; they then disperse throughout the cytoplasm. The endoplasmic reticulum. The ribosomes are composed of a lysosomes provide an intracellular digestive system that mixture of RNA and proteins; they function to synthesize allows the cell to digest the following: (1) damaged cellu- new protein molecules in the cell, as discussed later in this lar structures; (2) food particles that have been ingested chapter and in Chapter 3.␣ by the cell; and (3) unwanted matter such as bacteria. Lysosome are different in various cell types but are usu- Smooth (Agranular) Endoplasmic Reticulum. Part of ally 250 to 750 nanometers in diameter. They are sur- the endoplasmic reticulum has no attached ribosomes. rounded by typical lipid bilayer membranes and are filled This part is called the smooth, or agranular, endoplasmic with large numbers of small granules, 5 to 8 nanometers reticulum. The smooth reticulum functions for the syn- in diameter, which are protein aggregates of as many as thesis of lipid substances and for other processes of the 40 different hydrolase (digestive) enzymes. A hydrolytic cells promoted by intrareticular enzymes.␣ enzyme is capable of splitting an organic compound into two or more parts by combining hydrogen from a water Golgi Apparatus molecule with one part of the compound and combin- The Golgi apparatus, shown in Figure 2-5, is closely ing the hydroxyl portion of the water molecule with the related to the endoplasmic reticulum. It has membranes other part of the compound. For example, protein is similar to those of the smooth endoplasmic reticulum. hydrolyzed to form amino acids, glycogen is hydrolyzed The Golgi apparatus is usually composed of four or more to form glucose, and lipids are hydrolyzed to form fatty stacked layers of thin, flat, enclosed vesicles lying near one acids and glycerol. side of the nucleus. This apparatus is prominent in secre- Hydrolytic enzymes are highly concentrated in lyso- tory cells, where it is located on the side of the cell from somes. Ordinarily, the membrane surrounding the lyso- which secretory substances are extruded. some prevents the enclosed hydrolytic enzymes from The Golgi apparatus functions in association with the coming into contact with other substances in the cell and endoplasmic reticulum. As shown in Figure 2-5, small therefore prevents their digestive actions. However, some transport vesicles (also called endoplasmic reticulum conditions of the cell break the membranes of lysosomes, vesicles [ER vesicles]) continually pinch off from the endo- allowing release of the digestive enzymes. These enzymes plasmic reticulum and shortly thereafter fuse with the then split the organic substances with which they come Golgi apparatus. In this way, substances entrapped in ER in contact into small, highly diffusible substances such as 17 UNIT I Introduction to Physiology: The Cell and General Physiology Secretory Outer membrane granules Inner membrane Cristae Matrix Oxidative phosphorylation Outer chamber enzymes Figure 2-6. Secretory granules (secretory vesicles) in acinar cells of the pancreas. Figure 2-7. Structure of a mitochondrion. amino acids and glucose. Some of the specific functions of Mitochondria are present in all areas of each cell’s lysosomes are discussed later in this chapter.␣ cytoplasm, but the total number per cell varies from less than 100 up to several thousand, depending on the energy Peroxisomes requirements of the cell. Cardiac muscle cells (cardiomyo- Peroxisomes are physically similar to lysosomes, but cytes), for example, use large amounts of energy and have they are different in two important ways. First, they are far more mitochondria than fat cells (adipocytes), which believed to be formed by self-replication (or perhaps by are much less active and use less energy. Furthermore, budding off from the smooth endoplasmic reticulum) the mitochondria are concentrated in those portions rather than from the Golgi apparatus. Second, they con- of the cell responsible for the major share of its energy tain oxidases rather than hydrolases. Several of the oxi- metabolism. They are also variable in size and shape. dases are capable of combining oxygen with hydrogen Some mitochondria are only a few hundred nanometers ions derived from different intracellular chemicals to in diameter and are globular in shape, whereas others are form hydrogen peroxide (H2O2). Hydrogen peroxide is a elongated and are as large as 1 micrometer in diameter highly oxidizing substance and is used in association with and 7 micrometers long. Still others are branching and catalase, another oxidase enzyme present in large quan- filamentous. tities in peroxisomes, to oxidize many substances that The basic structure of the mitochondrion, shown might otherwise be poisonous to the cell. For example, in Figure 2-7, is composed mainly of two lipid bilayer- about half the alcohol that a person drinks is detoxified protein membranes, an outer membrane and an inner into acetaldehyde by the peroxisomes of the liver cells in membrane. Many infoldings of the inner membrane form this manner. A major function of peroxisomes is to catab- shelves or tubules called cristae onto which oxidative olize long-chain fatty acids.␣ enzymes are attached. The cristae provide a large surface area for chemical reactions to occur. In addition, the inner Secretory Vesicles cavity of the mitochondrion is filled with a matrix that One of the important functions of many cells is secretion contains large quantities of dissolved enzymes necessary of special chemical substances. Almost all such secretory for extracting energy from nutrients. These enzymes oper- substances are formed by the endoplasmic reticulum– ate in association with oxidative enzymes on the cristae Golgi apparatus system and are then released from the to cause oxidation of nutrients, thereby forming carbon Golgi apparatus into the cytoplasm in the form of stor- dioxide and water and, at the same time, releasing energy. age vesicles called secretory vesicles or secretory granules. The liberated energy is used to synthesize a high-energy Figure 2-6 shows typical secretory vesicles inside pancre- substance called adenosine triphosphate (ATP). ATP is atic acinar cells; these vesicles store protein proenzymes then transported out of the mitochondrion and diffuses (enzymes that are not yet activated). The proenzymes are throughout the cell to release its own energy wherever it secreted later through the outer cell membrane into the is needed for performing cellular functions. The chemical pancreatic duct and then into the duodenum, where they details of ATP formation by the mitochondrion are pro- become activated and perform digestive functions on the vided in Chapter 68, but some basic functions of ATP in food in the intestinal tract.␣ the cell are introduced later in this chapter. Mitochondria are self-replicative, which means that Mitochondria one mitochondrion can form a second one, a third one, The mitochondria, shown in Figure 2-2 and Figure 2-7, and so on whenever the cell needs increased amounts are called the powerhouses of the cell. Without them, cells of ATP. Indeed, the mitochondria contain DNA similar would be unable to extract enough energy from the nutri- to that found in the cell nucleus. In Chapter 3, we will ents, and essentially all cellular functions would cease. see that DNA is the basic constituent of the nucleus that 18  Chapter 2 The Cell and Its Functions α-Tubulin β-Tubulin monomer monomer Endoplasmic Ribosome Cell membrane Microfilaments reticulum Microtubule (25 nm) UNIT I Fibrous protein dimer Intermediate filament (8-12 nm) Microtubule Microfilament (7 nm) Mitochondrion Two intertwined F-actin chains G-actin monomer Intermediate filament Figure 2-8. Cell cytoskeleton composed of protein fibers called microfilaments, intermediate filaments, and microtubules. controls replication of the cell. The DNA of the mitochon- All cells have intermediate filaments, although the pro- drion plays a similar role, controlling replication of the tein subunits of these structures vary, depending on the mitochondrion. Cells that are faced with increased energy cell type. Specific intermediate filaments found in various demands—for example, in skeletal muscles subjected to cells include desmin filaments in muscle cells, neurofila- chronic exercise training—may increase the density of ments in neurons, and keratins in epithelial cells. mitochondria to supply the additional energy required.␣ A special type of stiff filament composed of polym- erized tubulin molecules is used in all cells to construct Cell Cytoskeleton—Filament and Tubular strong tubular structures, the microtubules. Figure 2-8 Structures shows typical microtubules of a cell. The cell cytoskeleton is a network of fibrillar proteins Another example of microtubules is the tubular skeletal organized into filaments or tubules. These originate as structure in the center of each cilium that radiates upward precursor proteins synthesized by ribosomes in the cyto- from the cell cytoplasm to the tip of the cilium. This struc- plasm. The precursor molecules then polymerize to form ture is discussed later in the chapter (see Figure 2-18). Also, filaments (Figure 2-8). As an example, large numbers of both the centrioles and mitotic spindles of cells undergoing actin microfilaments frequently occur in the outer zone mitosis are composed of stiff microtubules. of the cytoplasm, called the ectoplasm, to form an elas- A major function of microtubules is to act as a cyto- tic support for the cell membrane. Also, in muscle cells, skeleton, providing rigid physical structures for certain actin and myosin filaments are organized into a special parts of cells. The cell cytoskeleton not only determines contractile machine that is the basis for muscle contrac- cell shape but also participates in cell division, allows cells tion, as discussed in Chapter 6. to move, and provides a tracklike system that directs the Intermediate filaments are generally strong ropelike movement of organelles in the cells. Microtubules serve filaments that often work together with microtubules, as the conveyor belts for the intracellular transport of providing strength and support for the fragile tubulin vesicles, granules, and organelles such as mitochondria.␣ structures. They are called intermediate because their average diameter is between that of narrower actin micro- Nucleus filaments and wider myosin filaments found in muscle The nucleus is the control center of the cell and sends cells. Their functions are mainly mechanical, and they are messages to the cell to grow and mature, replicate, or less dynamic than actin microfilaments or microtubules. die. Briefly, the nucleus contains large quantities of DNA, 19 UNIT I Introduction to Physiology: The Cell and General Physiology Pores 15 nm: Small virus Endoplasmic 150 nm: Large virus reticulum Nucleoplasm 350 nm: Rickettsia Nucleolus 1 µm Bacterium Nuclear envelope: outer and inner membranes Cell Chromatin material (DNA) Cytoplasm 5-10 µm+ Figure 2-9. Structure of the nucleus. Figure 2-10. Comparison of sizes of precellular organisms with that of the average cell in the human body. which comprise the genes. The genes determine the char- acteristics of the cell’s proteins, including the structural RNA and proteins of the types found in ribosomes. The proteins, as well as the intracellular enzymes that control nucleolus enlarges considerably when the cell is actively cytoplasmic and nuclear activities. synthesizing proteins. The genes also control and promote cell reproduction. Formation of the nucleoli (and of the ribosomes in The genes first reproduce to create two identical sets of the cytoplasm outside the nucleus) begins in the nucleus. genes; then the cell splits by a special process called mito- First, specific DNA genes in the chromosomes cause sis to form two daughter cells, each of which receives one RNA to be synthesized. Some of this synthesized RNA is of the two sets of DNA genes. All these activities of the stored in the nucleoli, but most of it is transported out- nucleus are discussed in Chapter 3. ward through the nuclear pores into the cytoplasm. Here Unfortunately, the appearance of the nucleus under the it is used in conjunction with specific proteins to assemble microscope does not provide many clues to the mecha- “mature” ribosomes that play an essential role in forming nisms whereby the nucleus performs its control activities. cytoplasmic proteins, as discussed in Chapter 3.␣ Figure 2-9 shows the light microscopic appearance of the interphase nucleus (during the period between mitoses), COMPARISON OF THE ANIMAL CELL revealing darkly staining chromatin material throughout WITH PRECELLULAR FORMS OF LIFE the nucleoplasm. During mitosis, the chromatin material organizes in the form of highly structured chromosomes, The cell is a complicated organism that required many which can then be easily identified using the light micro- hundreds of millions of years to develop after the earli- scope, as illustrated in Chapter 3. est forms of life, microorganisms that may have been similar to present-day viruses, first appeared on earth. Nuclear Membrane. The nuclear membrane, also called Figure 2-10 shows the relative sizes of the following: (1) the nuclear envelope, is actually two separate bilayer the smallest known virus; (2) a large virus; (3) a Rickett- membranes, one inside the other. The outer membrane sia; (4) a bacterium; and (5) a nucleated cell, This dem- is continuous with the endoplasmic reticulum of the cell onstrates that the cell has a diameter about 1000 times cytoplasm, and the space between the two nuclear mem- that of the smallest virus and therefore a volume about 1 branes is also continuous with the space inside the endo- billion times that of the smallest virus. Correspondingly, plasmic reticulum, as shown in Figure 2-9. the functions and anatomical organization of the cell are The nuclear membrane is penetrated by several thou- also far more complex than those of the virus. sand nuclear pores. Large complexes of proteins are The essential life-giving constituent of the small virus is attached at the edges of the pores so that the central area a nucleic acid embedded in a coat of protein. This nucleic of each pore is only about 9 nanometers in diameter. acid is composed of the same basic nucleic acid constit- Even this size is large enough to allow molecules up to a uents (DNA or RNA) found in mammalian cells and is molecular weight of 44,000 to pass through with reason- capable of reproducing itself under appropriate condi- able ease.␣ tions. Thus, the virus propagates its lineage from genera- tion to generation and is therefore a living structure in the Nucleoli and Formation of Ribosomes. The nuclei of same way that cells and humans are living structures. most cells contain one or more highly staining structures As life evolved, other chemicals in addition to nucleic called nucleoli. The nucleolus, unlike most other orga- acid and simple proteins became integral parts of the nelles discussed here, does not have a limiting membrane. organism, and specialized functions began to develop Instead, it is simply an accumulation of large amounts of in different parts of the virus. A membrane formed 20  Chapter 2 The Cell and Its Functions around the virus and, inside the membrane, a fluid matrix Proteins Receptors appeared. Specialized chemicals then developed inside Coated pit Clathrin the fluid to perform special functions; many protein enzymes appeared that were capable of catalyzing chemi- cal reactions, thus determining the organism’s activities. In still later stages of life, particularly in the rickett- UNIT I sial and bacterial stages, organelles developed inside the A B organism. These represent physical structures of chemi- cal aggregates that perform functions in a more efficient Actin and myosin Dissolving clathrin manner than what can be achieved by dispersed chemi- cals throughout the fluid matrix. Finally, in the nucleated cell, still more complex organ- elles developed, the most important of which is the nucleus. The nucleus distinguishes this type of cell from all lower forms of life; it provides a control center for all C D cellular activities and for reproduction of new cells gen- Figure 2-11. Mechanism of pinocytosis. eration after generation, with each new cell having almost exactly the same structure as its progenitor.␣ Pinocytosis is the only means whereby most large macromolecules, such as most proteins, can enter cells. In fact, the rate at which pinocytotic vesicles form is usu- FUNCTIONAL SYSTEMS OF THE CELL ally enhanced when such macromolecules attach to the In the remainder of this chapter, we discuss some func- cell membrane. tional systems of the cell that make it a living organism. Figure 2-11 demonstrates the successive steps of pinocytosis (A–D), showing three molecules of protein attaching to the membrane. These molecules usually ENDOCYTOSIS—INGESTION BY THE CELL attach to specialized protein receptors on the surface of If a cell is to live and grow and reproduce, it must obtain the membrane that are specific for the type of protein nutrients and other substances from the surrounding flu- that is to be absorbed. The receptors generally are con- ids. Most substances pass through the cell membrane by centrated in small pits on the outer surface of the cell the processes of diffusion and active transport. membrane, called coated pits. On the inside of the cell Diffusion involves simple movement through the mem- membrane beneath these pits is a latticework of fibrillar brane caused by the random motion of the molecules of protein called clathrin, as well as other proteins, perhaps the substance. Substances move through cell membrane including contractile filaments of actin and myosin. Once pores or, in the case of lipid-soluble substances, through the protein molecules have bound with the receptors, the the lipid matrix of the membrane. surface properties of the local membrane change in such Active transport involves actually carrying a substance a way that the entire pit invaginates inward, and fibrillar through the membrane by a physical protein structure proteins surrounding the invaginating pit cause its bor- that penetrates all the way through the membrane. These ders to close over the attached proteins, as well as over a active transport mechanisms are so important to cell small amount of extracellular fluid. Immediately thereaf- function that they are presented in detail in Chapter 4. ter, the invaginated portion of the membrane breaks away Large particles enter the cell by a specialized func- from the surface of the cell, forming a pinocytotic vesicle tion of the cell membrane called endocytosis (Video 2-1). inside the cytoplasm of the cell. The principal forms of endocytosis are pinocytosis and What causes the cell membrane to go through the phagocytosis. Pinocytosis means the ingestion of minute necessary contortions to form pinocytotic vesicles is still particles that form vesicles of extracellular fluid and par- unclear. This process requires energy from within the cell, ticulate constituents inside the cell cytoplasm. Phagocyto- which is supplied by ATP, a high-energy substance dis- sis means the ingestion of large particles, such as bacteria, cussed later in this chapter. This process also requires the whole cells, or portions of degenerating tissue. presence of calcium ions in the extracellular fluid, which probably react with contractile protein filaments beneath Pinocytosis. Pinocytosis occurs continually in the cell the coated pits to provide the force for pinching the vesi- membranes of most cells, but is especially rapid in some cles away from the cell membrane.␣ cells. For example, it occurs so rapidly in macrophages that about 3% of the total macrophage membrane is en- Phagocytosis. Phagocytosis occurs in much the same gulfed in the form of vesicles each minute. Even so, the way as pinocytosis, except that it involves large particles pinocytotic vesicles are so small—usually only 100 to 200 rather than molecules. Only certain cells have the capa- nanometers in diameter—that most of them can be seen bility of phagocytosis—notably, tissue macrophages and only with an electron microscope. some white blood cells. 21 UNIT I Introduction to Physiology: The Cell and General Physiology Lysosomes proteins, carbohydrates, lipids, and other substances in the vesicle. The products of digestion are small molecules of substances such as amino acids, glucose, and phosphates that can diffuse through the membrane of the vesicle into the cytoplasm. What is left of the digestive vesicle, called Pinocytotic or the residual body, represents indigestible substances. In phagocytic most cases, the residual body is finally excreted through vesicle the cell membrane by a process called exocytosis, which is Digestive vesicle essentially the opposite of endocytosis. Thus, the pinocy- totic and phagocytic vesicles containing lysosomes can be called the digestive organs of the cells. Residual body Lysosomes and Regression of Tissues and Autolysis of Damaged Cells. Tissues of the body often regress to Excretion a smaller size. For example, this regression occurs in the uterus after pregnancy, in muscles during long periods of Figure 2-12. Digestion of substances in pinocytotic or phagocytic vesicles by enzymes derived from lysosomes. inactivity, and in mammary glands at the end of lactation. Lysosomes are responsible for much of this regression. Another special role of the lysosomes is the removal Phagocytosis is initiated when a particle such as a bac- of damaged cells or damaged portions of cells from tis- terium, dead cell, or tissue debris binds with receptors sues. Damage to the cell—caused by heat, cold, trauma, on the surface of the phagocyte. In the case of bacteria, chemicals, or any other factor—induces lysosomes to each bacterium is usually already attached to a specific rupture. The released hydrolases immediately begin to antibody; it is the antibody that attaches to the phago- digest the surrounding organic substances. If the damage cyte receptors, dragging the bacterium along with it. This is slight, only a portion of the cell is removed, and the cell intermediation of antibodies is called opsonization, which is then repaired. If the damage is severe, the entire cell is is discussed in Chapters 34 and 35. digested, a process called autolysis. In this way, the cell is Phagocytosis occurs in the following steps: completely removed, and a new cell of the same type is 1. The cell membrane receptors attach to the surface formed, ordinarily by mitotic reproduction of an adjacent ligands of the particle. cell to take the place of the old one. 2. The edges of the membrane around the points of The lysosomes also contain bactericidal agents that can attachment evaginate outward within a fraction of kill phagocytized bacteria before they cause cellular dam- a second to surround the entire particle; then, pro- age. These agents include the following: (1) lysozyme, which gressively more and more membrane receptors at- o dissolves the bacterial cell wall; (2) lysoferrin, which binds tach to the particle ligands. All this occurs suddenly iron and other substances before they can promote bacterial in a zipper-like manner to form a closed phagocytic growth; and (3) acid at a pH of about 5.0, which activates the vesicle. hydrolases and inactivates bacterial metabolic systems.␣ 3. Actin and other contractile fibrils in the cytoplasm surround the phagocytic vesicle and contract Autophagy and Recycling of Cell Organelles. around its outer edge, pushing the vesicle to the in- Lysosomes play a key role in the process of autophagy, terior. which literally means “to eat oneself.” Autophagy is 4. The contractile proteins then pinch the stem of the a housekeeping process whereby obsolete organelles vesicle so completely that the vesicle separates from and large protein aggregates are degraded and re- the cell membrane, leaving the vesicle in the cell in- cycled (Figure 2-13). Worn-out cell organelles are terior in the same way that pinocytotic vesicles are transferred to lysosomes by double-membrane struc- formed.␣ tures called autophagosomes, which are formed in the cytosol. Invagination of the lysosomal membrane and the formation of vesicles provides another pathway for LYSOSOMES DIGEST PINOCYTOTIC AND cytosolic structures to be transported into the lumen PHAGOCYTIC FOREIGN SUBSTANCES of lysosomes. Once inside the lysosomes, the orga- INSIDE THE CELL nelles are digested, and the nutrients are reused by the Almost immediately after a pinocytotic or phagocytic ves- cell. Autophagy contributes to the routine turnover of icle appears inside a cell, one or more lysosomes become cytoplasmic components; it is a key mechanism for attached to the vesicle and empty their acid hydrolases to tissue development, cell survival when nutrients are the inside of the vesicle, as shown in Figure 2-12. Thus, scarce, and maintenance of homeostasis. In liver cells, a digestive vesicle is formed inside the cell cytoplasm in for example, the average mitochondrion normally has which the vesicular hydrolases begin hydrolyzing the a life span of only about 10 days before it is destroyed.␣ 22  Chapter 2 The Cell and Its Functions Proteins Synthesis by the Rough Endoplasmic Reticu- lum. The rough endoplasmic reticulum is characterized by large numbers of ribosomes attached to the outer surfaces of the endoplasmic reticulum membrane. As discussed in Chapter 3, protein molecules are synthesized within the Isolation membrane structures of the ribosomes. The ribosomes extrude some VESICLE UNIT I NUCLEATION of the synthesized protein molecules directly into the cy- tosol, but they also extrude many more through the wall of the endoplasmic reticulum to the interior of the endo- plasmic vesicles and tubules into the endoplasmic matrix.␣ Lipid Synthesis by the Smooth Endoplasmic Reticu- lum. The endoplasmic reticulum also synthesizes lipids, AUTOSOME FORMATION especially phospholipids and cholesterol. These lipids are rapidly incorporated into the lipid bilayer of the endoplas- mic reticulum, thus causing the endoplasmic reticulum to Autophagosome grow more extensive. This process occurs mainly in the smooth portion of the endoplasmic reticulum. To keep the endoplasmic reticulum from growing Lysosome beyond the needs of the cell, small vesicles called ER vesicles or transport vesicles continually break away from the smooth reticulum; most of these vesicles then migrate rapidly to the Golgi apparatus.␣ Other Functions of the Endoplasmic Reticulum. Other significant functions of the endoplasmic reticu- DOCKING AND lum, especially the smooth reticulum, include the fol- FUSION WITH Autolysosome LYSOSOME lowing: 1. It provides the enzymes that control glycogen breakdown when glycogen is to be used for energy. Lysosomal 2. It provides a vast number of enzymes that are ca- hydrolase pable of detoxifying substances, such as drugs, that might damage the cell. It achieves detoxification by processes such as coagulation, oxidation, hydroly- sis, and conjugation with glycuronic acid.␣ VESICLE BREAKDOWN AND DEGRADATION Golgi Apparatus Functions Synthetic Functions of the Golgi Apparatus. Although Figure 2-13. Schematic diagram of autophagy steps. a major function of the Golgi apparatus is to provide ad- ditional processing of substances already formed in the SYNTHESIS OF CELLULAR STRUCTURES BY endoplasmic reticulum, it can also synthesize certain ENDOPLASMIC RETICULUM AND GOLGI carbohydrates that cannot be formed in the endoplas- APPARATUS mic reticulum. This is especially true for the formation of large saccharide polymers bound with small amounts of Endoplasmic Reticulum Functions protein; important examples include hyaluronic acid and The extensiveness of the endoplasmic reticulum and Golgi chondroitin sulfate. apparatus in secretory cells has already been emphasized. A few of the many functions of hyaluronic acid and These structures are formed primarily of lipid bilayer chondroitin sulfate in the body are as follows: (1) they membranes, similar to the cell membrane, and their walls are the major components of proteoglycans secreted in are loaded with protein enzymes that catalyze the synthe- mucus and other glandular secretions; (2) they are the sis of many substances required by the cell. major components of the ground substance, or nonfibrous Most synthesis begins in the endoplasmic reticulum. components of the extracellular matrix, outside the cells The products formed there are then passed on to the Golgi in the interstitial spaces, which act as fillers between col- apparatus, where they are further processed before being lagen fibers and cells; (3) they are principal components of released into the cytoplasm. First, however, let us note the the organic matrix in both cartilage and bone; and (4) they specific products that are synthesized in specific portions are important in many cell activities, including migration of the endoplasmic reticulum and Golgi apparatus. and proliferation.␣ 23 UNIT I Introduction to Physiology: The Cell and General Physiology Protein Lipid Secretory Types of Vesicles Formed by the Golgi Apparatus— Ribosomes formation formation Lysosomes vesicles Secretory Vesicles and Lysosomes. In a highly secre- tory cell, the vesicles formed by the Golgi apparatus are mainly secretory vesicles containing proteins that are se- creted through the surface of the cell membrane. These secretory vesicles first diffuse to the cell membrane and then fuse with it and empty their substances to the exte- rior by the mechanism called exocytosis. Exocytosis, in most cases, is stimulated by entry of calcium ions into the cell. Calcium ions interact with the vesicular mem- brane and cause its fusion with the cell membrane, fol- lowed by exocytosis—opening of the membrane’s outer surface and extrusion of its contents outside the cell. Some vesicles, however, are destined for intracellular Transport use.␣ Glycosylation vesicles Rough Smooth Golgi Use of Intracellular Vesicles to Replenish Cellular endoplasmic endoplasmic apparatus Membranes. Some intracellular vesicles formed by the reticulum reticulum Golgi apparatus fuse with the cell membrane or with the Figure 2-14. Formation of proteins, lipids, and cellular vesicles by the membranes of intracellular structures such as the mito- endoplasmic reticulum and Golgi apparatus. chondria and even the endoplasmic reticulum. This fusion increases the expanse of these membranes and replenish- Processing of Endoplasmic Secretions by the Golgi es the membranes as they are used up. For example, the Apparatus—Formation of Vesicles. Figure 2-14 sum- cell membrane loses much of its substance every time it marizes the major functions of the endoplasmic reticu- forms a phagocytic or pinocytotic vesicle, and the vesicu- lum and Golgi apparatus. As substances are formed in lar membranes of the Golgi apparatus continually replen- the endoplasmic reticulum, especially proteins, they are ish the cell membrane. transported through the tubules toward portions of the In summary, the membranous system of the endo- smooth endoplasmic reticulum that lie nearest to the plasmic reticulum and Golgi apparatus are highly Golgi apparatus. At this point, transport vesicles com- metabolic and capable of forming new intracellular posed of small envelopes of smooth endoplasmic retic- structures and secretory substances to be extruded ulum continually break away and diffuse to the deepest from the cell.␣ layer of the Golgi apparatus. Inside these vesicles are synthesized proteins and other products from the endo- THE MITOCHONDRIA EXTRACT ENERGY plasmic reticulum. FROM NUTRIENTS The transport vesicles instantly fuse with the Golgi apparatus and empty their contained substances into The principal substances from which cells extract energy the vesicular spaces of the Golgi apparatus. Here, are foods that react chemically with oxygen—carbo- additional carbohydrate moieties are added to the hydrates, fats, and proteins. In the human body, essen- secretions. Also, an important function of the Golgi tially all carbohydrates are converted into glucose by the apparatus is to compact the endoplasmic reticular digestive tract and liver before they reach the other cells secretions into highly concentrated packets. As the of the body. Similarly, proteins are converted into amino secretions pass toward the outermost layers of the acids, and fats are converted into fatty acids. Figure 2-15 Golgi apparatus, the compaction and processing pro- shows oxygen and the foodstuffs—glucose, fatty acids, ceed. Finally, both small and large vesicles continually and amino acids—all entering the cell. Inside the cell, break away from the Golgi apparatus, carrying with they react chemically with oxygen under the influence them the compacted secretory substances and diffus- of enzymes that control the reactions and channel the ing throughout the cell. energy released in the proper direction. The details of all The following example provides an idea of the tim- these digestive and metabolic functions are provided in ing of these processes. When a glandular cell is bathed Chapters 63 through 73. in amino acids, newly formed protein molecules can be Briefly, almost all these oxidative reactions occur detected in the granular endoplasmic reticulum within 3 inside the mitochondria, and the energy that is released to 5 minutes. Within 20 minutes, newly formed proteins is used to form the high-energy compound ATP. Then, are already present in the Golgi apparatus and, within 1 ATP, not the original food, is used throughout the cell to to 2 hours, the proteins are secreted from the surface of energize almost all the subsequent intracellular metabolic the cell.␣ reactions. 24  Chapter 2 The Cell and Its Functions the cell’s other functions, such as syntheses of substances 2ADP 2ATP and muscular contraction. To reconstitute the cellular ATP as it is used up, energy Glucose Fatty acids Gl FA ⑧36 ADP derived from the cellular nutrients causes ADP and phos- phoric acid to recombine to form new ATP, and the entire Amino acids AA Pyruvic acid process is repeated over and over. For these reasons, ATP UNIT I Acetoacetic has been called the energy currency of the cell because it acid can be spent and reformed continually, having a turnover ↓ Acetyl-CoA time of only a few minutes. O2 O2 O2 ADP CO2 CO2 CO2 + H2O ATP Chemical Processes in the Formation of ATP—Role of the Mitochondria. On entry into the cells, glucose is↳ converted by enzymes in the cytoplasm into pyruvic acid H2O H2O ·36 ATP (a process called glycolysis). A small amount of ADP is changed into ATP by the energy released during this con- Mitochondrion version, but this amount accounts for less than 5% of the Cell membrane Cytoplasm overall energy metabolism of the cell. About 95% of the cell’s ATP formation occurs in the Figure 2-15. Formation of adenosine triphosphate (ATP) in the cell mitochondria. The pyruvic acid derived from carbo- showing that most of the ATP is formed in the mitochondria. (ADP, Adenosine diphosphate; CoA, coenzyme A.) hydrates, fatty acids from lipids, and amino acids from proteins is eventually converted into the compound acetyl-coenzyme A (CoA) in the matrix of mitochondria. Functional Characteristics of Adenosine This substance, in turn, is further dissolved (for the pur- Triphosphate pose of extracting its energy) by another series of enzymes ⑧ 10 NH2 in the mitochondrion matrix, undergoing dissolution in a sequence of chemical reactions called the citric acid cycle, N C or Krebs cycle. These chemical reactions are so important C N HC Adenine that they are explained in detail in Chapter 68. C CH In this citric acid cycle, acetyl-CoA is split into its N N O O O component parts, hydrogen atoms and carbon dioxide. 1 · O CH2 O P O~P O~P O– The carbon dioxide diffuses out of the mitochondria and eventually out of the cell; finally, it is excreted from the C H H C O– O– O– body through the lungs. Phosphate H C C H The hydrogen atoms, conversely, are highly reactive; Gcombine with oxygen that has also diffused into they OH OH the mitochondria. This combination releases a tremen- Ribose dous amount of energy, which is o used by mitochondria Adenosine triphosphate to convert large amounts of ADP to ATP. The processes of these reactions are complex, requiring the participa- ATP is a nucleotide composed of the following: (1) the tion of many protein enzymes that are integral parts of nitrogenous base adenine; (2) the pentose sugar ribose; mitochondrial membranous shelves that protrude into the and (3) three phosphate radicals. The last two phosphate mitochondrial matrix. The initial event is the removal of radicals are connected with the remainder of the mol- an electron from the hydrogen atom, thus converting it to ecule by high-energy phosphate bonds, which are rep- back tubules remain stationary, bending occurs. - Basal plate The way in which cilia contraction is controlled is not well understood. The cilia of some genetically abnormal Cell membrane cells do not have the two central single tubules, and these Backward stroke cilia fail to beat. Therefore, it is presumed that some signal, Basal body perhaps an electrochemical signal, is transmitted along these two central tubules to activate the dynein arms.␣ Rootlet Nonmotile Primary Cilia Serve as Cell Sensory “An- tennae.” Primary cilia are nonmotile and generally occur only as a single cilium on each cell. Although the physiological functions of primary cilia are not fully un- Figure 2-18. Structure and function of the cilium. (Modified from derstood, current evidence indicates that they function Satir P: Cilia. Sci Am 204:108, 1961.) as cellular ‘’sensory antennae,” which coordinate cellular signaling pathways involved in chemical and mechani- In the inset of Figure 2-18, movement of the motile cal sensation, signal transduction, and cell growth. In the cilium is shown. The cilium moves forward with a sudden, - kidneys, for example, primary cilia are found in most epi- rapid whiplike stroke 10 to 20 times per second, bending thelial cells of the tubules, projecting into the tubule lu- sharply where it projects from the surface of the cell. Then men and acting as a flow sensor. In response to fluid flow it moves backward slowly to its initial position. The rapid, over the tubular epithelial cells, the primary cilia bend and forward-thrusting, whiplike movement pushes the fluid cause flow-induced changes in intracellular calcium sign- lying adjacent to the cell in the direction that the cilium aling. These signals, in turn, initiate multiple effects on moves; the slow dragging movement in the backward the cells. Defects in signaling by primary cilia in renal tu- direction has almost no effect on fluid movement. As a bular epithelial cells are thought to contribute to various result, the fluid is continually propelled in the direction of disorders, including the development of large fluid-filled the fast-forward stroke. Because most motile ciliated cells cysts, a condition called polycystic kidney disease. have large numbers of cilia on their surfaces, and because all the cilia are oriented in the same direction, this is an effective means for moving fluids from one part of the Bibliography surface to another. Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, 6th ed. New York: Garland Science, 2014. Mechanism of Ciliary Movement. Although not all Brandizzi F, Barlowe C: Organization of the ER-Golgi interface for membrane traffic control. Nat Rev Mol Cell Biol 14:382, 2013. aspects of ciliary movement are known, we are aware Dikic I, Elazar Z. Mechanism and medical implications of mammalian of the following elements.①First, the nine double tubules autophagy. Nat Rev Mol Cell Biol 19:349, 2018. and two single tubules are all linked to one another by a Eisner V, Picard M, Hajnóczky G. Mitochondrial dynamics in adap- complex of protein cross-linkages; this total complex of tive and maladaptive cellular stress responses. Nat Cell Biol 20:755, tubules and cross-linkages is called the axoneme. ② Second, 2018. Galluzzi L, Yamazaki T, Kroemer G. Linking cellular stress responses even after removal of the membrane and destruction of to systemic homeostasis. Nat Rev Mol Cell Biol 19:731, 2018. other elements of the cilium in addition to the axoneme, 28  Chapter 2 The Cell and Its Functions Guerriero CJ, Brodsky JL: The delicate balance between secreted pro- Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy tein folding and endoplasmic reticulum-associated degradation in in cellular homeostasis, physiology and pathology. Nat Cell Biol human physiology. Physiol Rev 92:537, 2012. 20:1013, 2018. Harayama T, Riezman H. Understanding the diversity of membrane Sezgin E, Levental I, Mayor S, Eggeling C. The mystery of membrane lipid composition. Nat Rev Mol Cell Biol 19:281, 2018. organization: composition, regulation and roles of lipid rafts. Nat Insall R: The interaction between pseudopods and extracellular signal- Rev Mol Cell Biol 18:361, 2017. ling during chemotaxis and directed migration. Curr Opin Cell Biol Spinelli JB, Haigis MC. The multifaceted contributions of mitochon- UNIT I 25:526, 2013. dria to cellular metabolism. Nat Cell Biol. 20:745, 2018. Kaksonen M, Roux A. Mechanisms of clathrin-mediated endocytosis. Walker CL, Pomatto LCD, Tripathi DN, Davies KJA. Redox regulation Nat Rev Mol Cell Biol 19:313, 2018. of homeostasis and proteostasis in peroxisomes. Physiol Rev 98:89, Lawrence RE, Zoncu R. The lysosome as a cellular centre for signalling, 2018. metabolism and quality control. Nat Cell Biol 21: 133, 2019. Zhou K, Gaullier G, Luger K. Nucleosome structure and dynamics are Nakamura N, Wei JH, Seemann J: Modular organization of the mam- coming of age. Nat Struct Mol Biol 26:3, 2019. malian Golgi apparatus. Curr Opin Cell Biol 24:467, 2012. 29