Cell and Tissue Structure 2023 PDF

CELL BIOLOGY Dr. Robert Formosa TOPICS TO BE COVERED What is the cell? What are cells composed of (organelles): The nucleus ribosomes Rough and smooth endoplasmic reticulum (ER) Golgi Apparatus Lysosomes Peroxisomes Cytoskeleton Cell membrane Intercellular Connections: tight, gap and adherense ju...

CELL BIOLOGY Dr. Robert Formosa TOPICS TO BE COVERED What is the cell? What are cells composed of (organelles): The nucleus ribosomes Rough and smooth endoplasmic reticulum (ER) Golgi Apparatus Lysosomes Peroxisomes Cytoskeleton Cell membrane Intercellular Connections: tight, gap and adherense junctions, desmosomes Specialized structures: cilia, pseudopodia and microvilli Organelle-associated diseases THE CELL Basic/smallest unit of all life! Human body made up of 37 trillion cells; making up about 210 different types of cells. Each cell is a functionally distinct unit that can: Grow Divide Generate energy (respiration) Communicate Excrete Respond to changes in environment Sometimes move WHY STUDY CELLS IN MEDICINE? All disease has a cellular aspect/mechanism Most genetic diseases alter basic cellular functions (cancer, autoimmune disease, etc) Progressive or chronic diseases alter cell structures and change the ability of cells of function properly or die altogether (heart disease, osteoporosis, arthritis, Parkinson’s, etc) The treatment of disease also focuses on the cell Drugs target specific receptors on cells Drugs target specific proteins in cells to switch them on or off Surgery also can alter cell structures and functional properties. ORGANELLES Division of labour Compartmentalization Increase efficiency Increase complexity Allow greater functions THE NUCLEUS Largest and most obvious, if not important organelle Functions: Storage of DNA (‘blueprint of life’) Expression of DNA – production of RNA/proteins Replication of DNA Regulates almost all functions of the cell DNA is stored complexed to protein – chromatin Surrounded by a double membrane, the nuclear envelope, which has pores (nuclear pores) that allow controlled transport of material (DNA, RNA, protein) in and out of nucleus. Which is the only cell type to lack a nucleus? THE NUCLEUS Nuclear Envelope: Separates nucleus from the rest of cytoplasm Inner layer has a network of fibres which give mechanical support to the membrane and are involved in DNA replication and cell division, called nuclear lamina. Outer membrane is continuous with the ER Nuclear Pores: Large protein complexes that span the 2 membranes Control what goes in and out of the nucleus, including: Ribosomal RNA Messenger RNA Proteins (enzymes that control DNA replication and transcription) carbohydrates THE NUCLEUS Nuclear Envelope: Separates nucleus from the rest of cytoplasm Inner layer has a network of fibres which give mechanical support to the membrane and are involved in DNA replication and cell division, called nuclear lamina. Outer membrane is continuous with the ER Nuclear Pores: Large protein complexes that span the 2 membranes Control what goes in and out of the nucleus, including: Ribosomal RNA Messenger RNA Proteins (enzymes that control DNA replication and transcription) carbohydrates LAMINOPATHIES There are about 8 rare human diseases with diverse manifestations. Some examples of laminopathies include Emery-Dreifuss muscular dystrophy and Progeria syndrome. Hutchinson-Gilford Progeria Syndrome – premature ageing. As the nuclear lamina normally provides support for organizing chromatin during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide. THE NUCLEUS The nucleolus: Generally a dense darker sphere in the nucleus Function: ribosomal (r)RNA transcription, rRNA processing and ribosomal assembly. Composed of nucleolar organizing regions made up of specific chromosomal segments. Heterochromatin & Euchromatin Heterochromatin: tightly-packed/condensed DNA Generally transcriptionally inactive (repressed). Euchromatin: more dispersed part of nucleus Less dense packing; open DNA unbound to protein Composed of transcriptionally active DNA THE NUCLEUS B C A THE NUCLEUS B A RIBOSOMES, ENDOPLASMIC RETICULUM & GOLGI APPARATUS All involved in the production of functional proteins and their delivery to the site of function RIBOSOMES Located either free in the cytoplasm or bound to the surface of the RER or nuclear envelope Made up of 2 subunits (60S and 40S) Composed of proteins and rRNA. Function: Synthesis of polypeptide chains (proteins) by attaching amino acids in a sequence as directed by DNA/RNA ENDOPLASMIC RETICULUM (ER) Composed of a membrane that is continuous with the nuclear envelope Forms folds of membranes called cisternae within which polypeptides are processed further. 2 types of ER: Rough endoplasmic reticulum (RER) Smooth endoplasmic reticulum (SER) RER RER derives its name from being covered in ribosomes on the outer surface. Polypeptide chains produced by the ribosomes enter immediately the RER, where they are folded into their specific 3D structure. In the RER most proteins are also tagged. Common tag is the addition of a carbohydrate, called glycosylation. Almost all cellular and secretory proteins are processed by the RER. Incorrect protein folding gives rise to a variety of diseases, including: prion diseases, Alzhiemer’s, Parkinson’s, sickle cell disease, cystic fibrosis. SER Distinguished from RER by the absence of ribosomes on the surface. Generally have specific functions in different cell types (ex. In muscles the SER stores calcium for contraction). Also important for the synthesis of carbohydrates and lipids within cell. Can breakdown lipids and synthesize new fatty acids. In kidney and liver cells also contain detoxifying enzymes. GOLGI APPARATUS Stacks membranes that modify and package proteins for transport to different areas of the cells (other organelles) or into secretory vesicles to be released outside the cell. RER vesicles Golgi apparatus Secretory vesicles SUMMARY SECRETORY PATHWAYS Commonly referred to as Exocytosis - Process by which cells release proteins into the extracellular environment through secretory vesicles. Exocytosis can be done through either of 3 pathways: 1. Constitutive secretion (ex. Release of extracellular matrix proteins) 2. Regulated secretion (or signal-mediated secretion) (ex. Release of hormones from endocrine cells) 3. Lysosomal secretion LYSOSOMES Produced by the Golgi apparatus Membrane –bound vesicles containing digestive enzymes. Enzymes in the lysosomes can either: Break down food or other organelles (autophagy) Breakdown invading organisms (bacteria, fungi) Breakdown the cell itself (autolysis) Defects in lysosomes: Lysosomal-storage diseases About 50 rare childhood diseases caused by genetic mutations Ex. Tay-Sachs disease- a genetic disease due to failure to break down lipids – causing death of neurons in brains and spinal cord. Caused by mutation in HEXA gene ENDOCYTOSIS Process by which substances/organisms can enter cells surrounded by a membrane formed from internal budding off of cell membrane. It is an energy-consuming process. 3 types of endocytosis: 1. Phagocytosis (‘cell eating’) 2. Pinocytosis (‘cell drinking’) 3. Receptor-mediated or clathrinmediated endocytosis PEROXISOMES Originate from the RER They are membrane bound vesicles containing a number of catalytic enzymes responsible mainly for the breakdown of fatty acids. Also contain the enzyme catalase needed for the breakdown of hydrogen peroxide which is a common by product of other enzyme activity in the peroxisome. Contain important detoxifying enzymes in the liver and kidney. Peroxisomal disorders: group of inherited rare metabolic diseases resulting from malfunctioning peroxisomes or their enzymes – result in accumulation of H2O2. Ex. Zellweger syndrome – absence of functional peroxisomes MITOCHONDRIA Responsible for energy production (ATP) of the cell ( TCA cycle & ETC) Has 2 double layered membranes (inner and outer) and folds called cristae. Also has its own DNA – mitochondrial DNA which codes for some (not all) protein functioning in the mitochondria. Important during the initiation of apoptosis (programmed cell death) Mitochondrial diseases: over 40 clinically heterogeneous diseases Most affect the muscle and nervous system (high energy demand systems) Disruption in energy production has vast effects on all systems. Can be caused by mutations in mitochondrial DNA (ex. Leber hereditary optic neuropathy) or nuclear DNA (ex. Leigh syndrome – X-linked) THE CYTOSKELETON Network of protein structures that maintain the physical integrity of the cell and allow for transport and movement of organelles and vesicles throughout the cell. Allow flexibility and movement within the cell but at the same time provide mechanical support and rigidity. Made up of 3 types of fibres: 1. microfilaments (made up of actin) 2. intermediate filaments 3. microtubules MICROFILAMENTS Made up of actin- the thinnest microfilament in the cells (3-6nm) Actin is globular protein but when assembled into filaments takes a different orientation Function of actin microfilaments: Mechanical support of cells (stress fibres) Allow movement of organelles & vesicles within the cell along actin microfilaments Allow cell movement together with myosin by forming filpodia (cytokinesis) In muscles, allow contraction together with myosin Actin-related diseases: Actin myopathies INTERMEDIATE FILAMENTS Intermediate in thickness between microfilaments and microtubules (10nm) Mainly involved in providing tensile strength whilst maintaining flexibility of the cell. Different cell types have different intermediate filaments made up of different protein components: Connective tissue – vimentin Nerves – neurofilaments Muscle – desmin Skin & epithelia – keratin Disease associated with keratin : Epidermolysis bulbosa – genetic condition leading to easy blistering of skin. MICROTUBULES Large tubular structures (10-25nm) which are generally hollow and made up of the protein tubulin (alpha & beta dimers) Have a number of functions including: Scaffolding on which organelles and vesicles can move along Form the framework of the mitotic spindle required for cell division (this can be a drug target used for cancer chemotherapy to prevent cell division) May also act as cilia or flagella in specialized cells to propel or move the cell in specific direction. Kinetochores supporting mitosis SUMMARY OF CYTOSKELETON PLASMA MEMBRANE • Forms the outside boundary of all cells and also internal vesicles and some organelles (ER, golgi, lysosomes, etc) • Basic structure: phospholipid bilayer with internal hydrophobic molecules and external hydrophilic molecules. • Can be highly complicated and dynamic and contain various proteins that either attach to the membrane (ex. internal enzymes) or span part of (ex. nuclear receptors) or completely the membrane (channel proteins) PLASMA MEMBRANE Functions of the plasma membrane: 1. Protection 2. Communication (receptors, antigen-presenting complexes) 3. Permeability (channels and pores) 4. Identification (immune checks) 5. Cell adhesion 6. Anchor cytoskeleton 7. Interaction with extra cellular matrix. TOPICS TO BE COVERED Intercellular connections (& relation to disease): Adherens junctions Tight junctions Gap junctions Desmosomes Specialized structures of the cell surface: Pseudopodia Cilia Microvilli BASAL LAMINA / BASEMENT MEMBRANE a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. The basement membrane is made of Type IV Collagen, Laminin, and a Heparan Sulfate Proteoglycan Functions: • provides structural support for the surrounding tissues, • relays functional messages • acts as a transit for various growth factors. • Serves as a physical barrier between epithelia and underlying connective tissues • May act as a molecular filter • Controls cell movement along the membrane. • Provides anchorage to the epithelia DISEASES OF THE BASAL MEMBRANE Epidermolysis Bulbosa – group of genetic conditions causing blistering of skin and membranes. Ex. Junctional epidermolysis bullosa – mutations in laminin (protein which interacts with collagens) Cancer: Malignant cancers undergo a epithelial – mesenchymal transition (EMT) In order for this to occur they must disrupt the ECM and break through the basal lamina to infiltrate nearby tissues and access the blood supply. blood vessel INTER-CELLULAR JUNCTIONS TIGHT JUNCTIONS Functions: Hold cells together Provide a physical barrier between outer side of cells and inner side (important to control selective transportation and osmotic balance) Prevent passage of ions and molecules between adjacent cells Prevent passage of bacteria and viruses from lumen/cavities into interstitial spaces Several diseases result in disruption of tight junctions, including Alzeihmer’s, Parkinson’s, multiple sclerosis, stroke and epilepsy. ADHERENS JUNCTIONS A cell junction whose cytoplasmic face is linked to the actin cytoskeleton. Generally found in epithelia and endothelial cells and are locally more basally than tight junctions Core is formed by cadherin molecules that adhere tightly to each other in the presence of calcium and bind catenin on the cytoplasmic side which connects them to the actin filaments of the cytoskeletons. Functions: Add robustness and plasticity to cells Help cells stick together strongly but also help during wound healing to facilitate cell contact DESMOSOMES Staphylococcus scalded-skin syndrome Like adherens junctions, they attach adjacent cells together and connect to keratin microfilaments of the cytoskeleton through specialized plaques on the inner side of the cell membrane. They are randomly arranged spots on the lateral sides of plasma membranes Function: Provide strong attachment between cells in tissues that have high mechanical stress such as cardiac tissues, bladder, intestinal mucosa and epithelia. Diseases: 1. Arrhythmogenic right ventricular cardiomyopathy is a disease caused by mutations in desmoglein gene resulting in defective desmosomes and can cause sudden death in young man. 2. Staphylococcus scalded-skin syndrome are the result of bacterial proteases directed at desmosomal cadherins and result in epidermal blisters 3. Pemphigus vulgaris: automimmune disease that attacks desmosomes causing blisters GAP JUNCTIONS specialized intercellular connection between a multitude of cell-types Form direct connections between the cytoplasm of 2 adjacent cells, allowing the regulated passage of molecules and ions between cells. Can be use to establish chemical and electric gradients between cells - ex. Vital in electrical conduction in cardiac muscle cells. Made up of complexes of proteins called connexin. 6 connexin molecules make up 1 connexon on either side gap junction (2 connexons – one on each cell side) Gap junctions are important in conducting information from one cell to the next. Ex. Death signals can travel from one cell to next causing apoptosis (called “bystander effect”) SUMMARY SPECIALIZED CELL SURFACES PSEUDOPODIA temporary cytoplasm-filled projection of the cell membrane Movement is caused by rearrangement of cytoskeleton Extension and reassembly of actin Contraction of myosin Functions: Used for motility Used for ingestion (phagocytosis) LAMELLIPODIA & FILOPODIA Lamellipodia are flat, broad protrusions that allow a cell to move forward and make contact with other cells and their environment. Filopodia are long thin protrusions that extend several micrometers ahead of the cells and are used to explore and sense the nearby environment to guide the cell and make contact with other cells. Both movements occur due to ATP –driven polymerization of actin filaments. Tumour cells tend to produce many filopodia to sense and invade their immediate environment. MICROVILLI Small extensions of the cell surface of absorptive and secretory epithelial cells, such as kidney and intestinal cells. (Brush Border) Function: Increase the surface area of cells by approximately 600 fold, for absorption and secretion. Microvilli often have enzymes that aid their function e.g., enzymes to help hydrolyze carbohydrates are present on microvilli in intestinal epithelial cells Microvilli are covered with glycocalyx consisting of peripheral glycoproteins that can attach themselves to a membrane. This layer may be used to aid binding of substances needed for uptake, to adhere nutrients or as protection against harmful elements. It can be another location for functional enzymes to be localized. Structure maintained by actin filaments MICROVILLI IN DISEASE 1. Infections (eg. Escherichia Coli), Celiac disease, and Microvillus Inclusion Disease (an inherited disease characterized by defective microvilli) – can disrupt the structure of the epithelial layer of the small intestine. Symptoms: Malabsorption of nutrients and persistent osmotic diarrhoea, often accompanied by fever, and a failure to thrive. 2. Toxins can lead to destruction of intestinal microvilli, intestinal tight junctions resulting in inhibition of waterreabsorption. 3. Congenital lack of microvilli in the intestinal tract causes microvillus atrophy, a rare, usually fatal condition found in new-born babies. CILIA slender protuberances that project from the much larger cell body. Generally divided in: motile and non-motile Depends on arrangement of microtubule organization within the cilium Non-motile – sensory surfaces (ears, mechanoreceptors) Motile – trachea (move mucus), fallopian tubes (move ova) Genetic ciliopathies - Bardet--Biedl Syndrome Primary ciliary disorders. Cilia defects adversely affect numerous critical developmental signaling pathways essential to cellular development TOPICS COVERED Connective tissue and the extra cellular matrix (ECM) Molecules of the ECM (proteoglycans, collagen, fibrous elements) Intercellular connections (& relation to disease): Adherens junctions Tight junctions Gap junctions Desmosomes Specialized structures of the cell surface: Pseudopodia Lamelipodia and filopodia Cilia Microvilli