Essentials of Medical Physiology K Sembulingam, Prema Sembulingam
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1General Physiology
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  1. Cell.
  2. Cell Junctions.
  3. Transport Through Cell Membrane.
  4. Homeostasis.
  5. Acid Base Balance.
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Cell1

  • ■ INTRODUCTION
    • ■ CELL
    • ■ TISSUES
    • ■ ORGANS
    • ■ SYSTEMS
  • ■ STRUCTURE OF THE CELL
  • ■ CELL MEMBRANE
    • ■ COMPOSITION
    • ■ STRUCTURE
    • ■ FUNCTIONS
  • ■ CYTOPLASM
  • ■ ORGANELLES IN CYTOPLASM
    • ■ ENDOPLASMIC RETICULUM
    • ■ GOLGI APPARATUS
    • ■ LYSOSOMES
    • ■ PEROXISOMES
    • ■ CENTROSOME AND CENTRIOLES
    • ■ SECRETORY VESICLES
    • ■ MITOCHONDRION
    • ■ RIBOSOMES
    • ■ CYTOSKELETON
  • ■ NUCLEUS
  • ■ DNA
  • ■ GENE
  • ■ RNA
  • ■ TRANSCRIPTION AND TRANSLATION
  • ■ GROWTH FACTORS
  • ■ CELL DEATH
    • ■ NECROSIS
    • ■ APOPTOSIS
 
■ INTRODUCTION
 
■ CELL
Cell is defined as the structural and functional unit of the living body. All the living things are composed of cells. A single cell is the smallest unit that has all the characteristics of life.
The general characteristics of a cell:
  1. Needs nutrition and oxygen
  2. Produces its own energy necessary for its growth and other activities and repair
  3. Eliminates carbon dioxide and other metabolic wastes
  4. Maintains the medium, i.e. the environment for its survival
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  5. Shows immediate response to the entrance of invaders like bacteria or toxic substances into the body
  6. Reproduces by division. There are some exceptions like neuron, which do not reproduce.
 
■ TISSUES
The tissue is defined as the group of cells having similar function. There are many types of tissues in the body. All the tissues are classified into four major types which are called the primary tissues. The primary tissues include:
  1. Muscle tissue – skeletal muscle, smooth muscle and cardiac muscle
  2. Nervous tissue – neurons and supporting cells
  3. Epithelial tissue – squamous, columnar and cuboidal epithelial cells
  4. Connective tissue – connective tissue proper, cartilage, bone and blood.
 
■ ORGANS
An organ is defined as the structure that is formed by two or more primary types of tissues, which execute the functions of the organ. Some organs are composed of all the four types of primary tissues. The organs are of two types called tubular or hollow organs and compact or parenchymal organs. Some of the organs in the body are brain, heart, lungs, stomach, intestine, liver, gallbladder, pancreas, kidneys, endocrine glands, etc.
 
■ SYSTEMS
The organ system is defined as group of organs that perform together to carryout specific functions of the body.
Each system performs a specific function. Digestive system is concerned with digestion of food particles. Excretory system eliminates unwanted substances. Cardiovascular system is responsible for transport of substances between the organs. Respiratory system is concerned with the supply of oxygen and removal of carbon dioxide. Reproductive system is involved in the reproduction of species. Endocrine system is concerned with growth of the body and the regulation and maintenance of normal life. Musculoskeletal system is responsible for stability and movements of the body. Nervous system controls the locomotion and other activities including the intellectual functions.
 
■ STRUCTURE OF THE CELL
Each cell is formed by a cell body and a membrane covering the cell body called the cell membrane. It is also known as plasma membrane. The cell membrane separates the cell body from the fluid surrounding the cell. The cell body has two parts namely the nucleus and the cytoplasm surrounding the nucleus (Fig. 1-1).
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FIGURE 1-1: Structure of the cell
Thus, the structure of the cell is studied under three headings:
  1. Cell membrane
  2. Cytoplasm
  3. Nucleus.
 
■ CELL MEMBRANE
The cell membrane is a protective sheath, enveloping the cell body. This membrane separates the fluid out side the cell called extracellular fluid (ECF) and the fluid inside the cell called intracellular fluid (ICF). The cell membrane is a semipermeable membrane. So, there is free exchange of certain substances between the ECF and ICF. The thickness of the cell membrane varies from 75Å to 111Å (Fig. 1-2).
 
■ COMPOSITION OF CELL MEMBRANE
The cell membrane is composed of three types of substances:
  1. Proteins (55%)
  2. Lipids (40%)
  3. Carbohydrates (5%).
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FIGURE 1-2: Diagram of the cell membrane
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■ STRUCTURE OF CELL MEMBRANE
On the basis of structure, the cell membrane is called a unit membrane or a three layered membrane. The electron microscopic study reveals three layers of cell membrane namely, one central electron-lucent layer and two electron-dense layers. The two electron-dense layers are placed one on either side of the central layer. The central layer is called lipid layer as it is formed by lipid substances. The outer two layers are formed by proteins and are called protein layers. Cell membrane contains some carbohydrate molecules also.
 
Structural Model of the Cell Membrane
 
1. Danielli-Davson model
‘Danielli-Davson model’ was the first proposed basic model of membrane structure and it was accepted by scientists for many years. This model was basically a ‘sandwich of lipids’ covered by proteins on both sides.
 
2. Unit membrane model
In 1957, JD Robertson replaced ‘Danielli-Davson model’ by ‘Unit membrane model’ on the basis of electron microscopic studies.
 
3. The fluid mosaic model
Later in 1972, SJ Singer and GL Nicholson proposed ‘The fluid mosaic model’. According to them the membrane is a fluid with mosaic of proteins (mosaic means pattern formed by arrangement of different colored pieces of stone, tile, glass or other such materials). This model is accepted by the scientists till now. In this model, the proteins are thought to float within the bilayered lipid instead of forming the layers of the sandwich type model.
 
Lipid Layer of the Cell Membrane
The central lipid layer is a bilayered structure. This is formed by a thin film of lipids. The major lipids are:
  1. Phospholipids
  2. Cholesterol.
 
1. Phospholipids
The phospholipids are the lipid substances containing phosphorus and fatty acids. The phospholipids of the lipid layer are amino phospholipids, sphingomyelins, phosphatidyl choline, phosphatidyl etholamine, phosphatidyl glycerol, phosphatidyl serine and phosphatidyl inositol.
The phospholipid molecules are arranged in two layers (Fig. 1-3). Each phospholipid molecule resembles the headed pin in shape. The outer part of the phospholipid molecule called head portion is soluble in water (hydrophilic). The inner part is the tail portion that is not soluble in water (hydrophobic).
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FIGURE 1-3: Lipids of the cell membrane
The two layers of phospholipids are arranged in such a way that the hydrophobic tail portions meet in the center of the membrane. The hydrophilic head portions of outer layer face the ECF and those of the inner layer face the cytoplasm.
 
2. Cholesterol
The cholesterol molecules are arranged in between the phospholipid molecules. The phospholipids are soft and oily structures, and cholesterol helps to “pack” the phospholipids in the membrane. So, cholesterol is responsible for the structural integrity of cell membrane.
The characteristic feature of lipid layer is that, it is fluid in nature and not a solid structure. So, the portions of the membrane move from one point to another point along the surface of the cell. The materials dissolved in lipid layer also move to all the areas of the cell membrane.
 
Functional Significance of Lipid Layer
The lipid layer of the cell membrane forms a semipermeable membrane. It allows only the fat soluble substances to pass through it. Thus, only the substances like oxygen, carbon dioxide and alcohol can pass through the lipid layer. And, this layer forms a barrier to the water soluble materials like glucose, urea and electrolytes.
 
Protein Layers of the Cell Membrane
The protein layers of the cell membrane are the electron-dense layers. These layers cover the two surfaces of the central lipid layer. The protein layers give protection to the watery central lipid layer. The protein substances present in these layers are mostly the glycoproteins. The 6protein molecules present in the cell membrane are classified into two categories:
  1. Integral proteins
  2. Peripheral proteins.
 
1. Integral proteins
The integral proteins are also known as transmembrane proteins. These proteins pass through the entire thickness of the cell membrane from one side to the other side. These proteins are tightly bound with the cell membrane.
 
2. Peripheral proteins
The peripheral proteins are otherwise called peripheral membrane proteins. These proteins are partially embedded in the outer and inner surfaces of the cell membrane and do not penetrate the cell membrane. The peripheral proteins are loosely bound with the cell membrane. So, these protein molecules dissociate readily from the cell membrane.
 
Functional Significance of Protein Layers
  1. Integral proteins: Integral proteins provide the structural integrity of the cell membrane.
  2. Channel proteins: Some integral protein molecules function as channels for the diffusion of water soluble substances like glucose and electrolytes. So, these proteins are called the channel proteins.
  3. Carrier proteins: Some protein molecules help in the transport of substances across the cell membrane by means of active or passive (facilitated diffusion) transport. These are called carrier proteins.
  4. Receptor proteins: Some protein molecules serve as the receptor sites for hormones and neurotransmitters. Such proteins are known as receptor proteins.
  5. Enzymes: Some of the protein molecules form the enzymes which control chemical (metabolic) reactions within the cell membrane.
  6. Antigens: Some proteins act as antigens and induce the process of antibody formation.
 
Carbohydrates of the Cell Membrane
Throughout the surface of cell membrane, there are some carbohydrates, which are attached to either the proteins or the lipids. The carbohydrates attached to proteins form glycoproteins (proteoglycans) and those attached to lipids form the glycolipids.
All these carbohydrate molecules form a thin loose covering over the entire surface of the cell membrane called glycocalyx.
 
Functional Significance of Carbohydrates
  1. The carbohydrate molecules are negatively charged and do not permit the negatively charged substances to move in and out of the cell.
  2. The glycocalyx from the neighboring cells helps in the tight fixation of cells with one another.
  3. Some of the carbohydrate molecules form the receptors for some hormones.
 
■ FUNCTIONS OF CELL MEMBRANE
  1. Protective function: The cell membrane protects the cytoplasm and the organelles present in the cytoplasm.
  2. Selective permeability: The cell membrane acts as a semipermeable membrane which allows only some substances to pass through it and acts as a barrier for other substances.
  3. Absorptive function: The nutrients are absorbed into the cell through the cell membrane.
  4. Excretory function: The metabolites and other waste products from the cell are excreted out through the cell membrane.
  5. Exchange of gases: Oxygen enters the cell from the blood and carbon dioxide leaves the cell and enters the blood through the cell membrane.
  6. Maintenance of shape and size of the cell: The cell membrane is responsible for the maintenance of shape and size of the cell.
 
■ CYTOPLASM
The cytoplasm is the fluid present inside the cell. It contains a clear liquid portion called cytosol and various particles of different shape and size. The particles are proteins, carbohydrates, lipids or electrolytes in nature. The cytoplasm also contains many organelles with distinct structure and function.
 
■ PARTS OF CYTOPLASM
The cytoplasm is made up of two zones namely ectoplasm and endoplasm. Ectoplasm is the peripheral part of cytoplasm just beneath the cell membrane. The endoplasm is interposed between the ectoplasm and the nucleus.
 
■ ORGANELLES IN CYTOPLASM
All the cells in the body contain some common structures called organelles in the cytoplasm. There is constant flow of materials between the organelles and cytoplasm. Some organelles are bound by limiting membrane and others do not have limiting membrane (Table 1-1). The organelles carryout the various functions of the cell (Table 1-2).7
TABLE 1-1   Cytoplasmic organelles
The organelles with limiting membrane vesicles
1. Endoplasmic reticulum
2. Golgi apparatus
3. Lysosome
4. Peroxisome
5. Centrosome and centrioles
6. Secretory vesicles
7. Mitochondria
8. Nucleus
The organelles without limiting membrane
1. Ribosomes
2. Cytoskeleton
 
■ 1. ENDOPLASMIC RETICULUM
Endoplasmic reticulum consists of tubular and microsomal vesicular structures, which are arranged in the form of interconnected network in the cytoplasm. It is covered by a limiting membrane which is formed by bilayered lipids and proteins. The lumen of endoplasmic reticulum contains a fluid medium called endoplasmic matrix. The diameter of the lumen is about 400 to 700Å. The endoplasmic reticulum forms the link between nucleus and cell membrane by connecting the cell membrane with nuclear membrane.
The endoplasmic reticulum is of two types namely, rough endoplasmic reticulum and smooth endoplasmic reticulum. Both the types are interconnected and continuous with one another. Depending upon the activities of the cells, the rough endoplasmic reticulum changes to smooth endoplasmic reticulum and vice versa.
TABLE 1-2   Functions of cytoplasmic organelles
Organelles
Functions
Rough endoplasmic reticulum
  1. Synthesis of proteins
  2. Degradation of worn out organelles
Smooth endoplasmic reticulum
  1. Synthesis of lipids and steroids
  2. Storage and metabolism of calcium
  3. Degradation of toxic substances
Golgi apparatus
Processing, packaging, labeling and delivery of proteins and lipids
Lysosomes
  1. Degradation of macromolecules like bacteria
  2. Degradation of worn out organelles
  3. Secretory function
Peroxisomes
  1. Degradation of toxic substances like hydrogen peroxide
  2. Oxygen utilization
  3. Breakdown of excess fatty acids
  4. Acceleration of gluconeogenesis from fats
  5. Degradation of purin to uric acid
  6. Role in the formation of myelin and bile acids
Centrosome
Movement of chromosomes during cell division
Mitochondria
  1. Production of energy
  2. Synthesis of ATP
  3. Initiation of apoptosis
Ribosomes
Synthesis of proteins
Cytoskeleton
  1. Determination of shape of the cell
  2. Stability of cell shape
  3. Cellular movements
Nucleus
  1. Control of all activities of the cell
  2. Synthesis of RNA
  3. Sending genetic instruction to cytoplasm for protein synthesis
  4. Formation of subunits of ribosomes
  5. Control of cell division
  6. Storage of hereditary information in genes (DNA)
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FIGURE 1-4: Endoplasmic reticulum
 
Rough Endoplasmic Reticulum
Rough endoplasmic reticulum is vesicular or tubular in structure. Granular ribosomes which are attached to the outer surface of this reticulum give the bumpy or bead like appearance. Hence, this part is also called the granular endoplasmic reticulum (Fig. 1-4).
 
Functions of rough endoplasmic reticulum
Rough endoplasmic reticulum is concerned with the synthesis of proteins in the cell. It is involved with the synthesis of mainly those proteins which are secreted from the cell such as insulin from β cells of islets of Langerhans in pancreas and antibodies in leukocytes.
The ribosomes arrange the amino acids into small units of proteins and transport them into the rough endoplasmic reticulum. Here, the carbohydrates are added to the proteins forming the glycosylated proteins or glycoproteins which are arranged in the form of reticular vesicles. These vesicles are transported mainly to Golgi apparatus for further modification and processing. Some of the vesicles are transported to other cytoplasmic organelles.
Rough endoplasmic reticulum also plays important role in degradation of worn out cytoplasmic organelles like mitochondria. It wraps itself around the worn out organelles and forms a vacuole which is often called the autophagosome. It is digested by lysosomal enzymes (see below for details).
 
Smooth Endoplasmic Reticulum
Smooth endoplasmic reticulum has a smooth appearance with out the attachment of ribosomes. It is also called agranular reticulum. It is formed by many interconnected tubules. So, it is also called tubular endoplasmic reticulum.
 
Functions of smooth endoplasmic reticulum
Smooth endoplasmic reticulum is responsible for synthesis of nonprotein substances such as cholesterol and steroid. This type of endoplasmic reticulum is abundant in cells that are involved in the synthesis of lipids, phospholipids, lipoprotein substances, steroid hormones, sebum, etc. In most of the other cells, smooth endoplasmic reticulum is less extensive than the rough endoplasmic reticulum. Many enzymes concerned with various metabolic processes of the cell are present on the outer surface of smooth endoplasmic reticulum.
Smooth endoplasmic reticulum is also involved in the storage and metabolism of calcium. In skeletal muscle fibers, it releases calcium which is necessary to trigger the muscle contraction. It is also concerned with catabolism and detoxification of toxic substances like some drugs and carcinogens (cancer producing substances) in liver.
 
■ 2. GOLGI APPARATUS
Golgi apparatus or Golgi body or Golgi complex is present in all the cells except red blood cells. It is situated near the nucleus. Usually, each cell has one Golgi apparatus. Some of the cells may have more than one Golgi apparatus. Each Golgi apparatus consists of 5 to 8 membranous sacs. The sacs are usually flattened and are called the cisternae.
The Golgi apparatus has two ends or faces namely, cis face and trans face. The cis face is positioned near the endoplasmic reticulum. The reticular vesicles from endoplasmic reticulum enter the Golgi apparatus through this face. The trans face is situated near the cell membrane. The processed substances make their exit from Golgi apparatus through this face (Fig. 1-5).
 
Functions of Golgi Apparatus
The major functions of Golgi apparatus are the processing and delivery of proteins and other molecules like lipids to different parts of the cell.
The vesicles containing glycoproteins and lipids are transported into Golgi apparatus from the reticuloendothelial system. In the Golgi apparatus, the glycoproteins and lipids are modified and processed.9
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FIGURE 1-5: Golgi apparatus
All the processed materials are packed in the form of secretory granules, secretory vesicles, and lysosomes which are transported either out of the cell or to another part of the cell. Because of this, it is called the post office of the cell.
Another important function of Golgi apparatus is to label (such as phosphate group depending up on the chemical content) and sort out the processed and packed materials for distribution to their proper destinations. Hence, the Golgi apparatus is also called the shipping department of the cell.
 
■ 3. LYSOSOMES
Lysosomes are the membrane bound vesicular organelles found throughout the cytoplasm. The lysosomes are formed by Golgi apparatus. The enzymes synthesized in rough endoplasmic reticulum are processed and packed in the form of small vesicles in the Golgi apparatus. Then, these vesicles are pinched off from Golgi apparatus and become the lysosomes.
Among the organelles of the cytoplasm, the lysosomes have the thickest covering membrane. The membrane is formed by bilayered lipid material. Many small granules are present in the lysosome. The granules contain the hydrolytic enzymes.
 
Types of Lysosomes
Lysosomes are of two types:
  1. Primary lysosome: It is the one that is pinched off from Golgi apparatus. In spite of having the hydrolytic enzymes, the primary lysosome is inactive
  2. Secondary lysosome: It is the active lysosome that is formed by the fusion of a primary lysosome with phagosome or endosome (see below).
 
Functions of Lysosomes
Two mechanisms are involved in the lysosomal functions:
  1. Heterophagy – digestion of extracellular materials engulfed by the cell via endocytosis
  2. Autophagy – digestion of intracellular materials such as worn out cytoplasmic organelles.
Lysosomes are often called ‘garbage system’ of the cell because of their degradation activity.
About 50 different hydrolytic enzymes, known as acid hydroxylases are present in the lysosomes.
Lysosomes execute their functions through these enzymes which include:
  1. Proteases which hydrolyze the proteins into amino acids
  2. Lipases which hydrolyze the lipids into fatty acids and glycerides
  3. Amylases which hydrolyze the polysaccharides into glucose
  4. Nucleases which hydrolyze the nucleic acids into mononucleotides.
The functions of lysosomes are:
 
i. Degradation of macromolecules
The macromolecules are engulfed by the cell by means of endocytosis (phagocytosis, pinocytosis or receptor mediated endocytosis - Chapter 3). The macromolecules like bacteria engulfed by the cell via phagocytosis are called phagosomes or vacuoles. The other macromolecules taken inside via pinocytosis or receptor mediated endocytosis are called endosomes. The primary lysosome fuses with the phagosome or endosome to form the secondary lysosome. The pH in the secondary lysosome becomes acidic and the lysosomal enzymes are activated. The bacteria and the other macromolecules are digested and degraded by these enzymes. The secondary lysosome containing theses degraded waste products moves through cytoplasm and fuses with cell membrane. Now the waster products are eliminated by exocytosis.
 
ii. Degradation of worn out organelles
The rough endoplasmic reticulum wraps itself around the worn out organelles like mitochondria and form the vacuoles called autophagosomes. One primary lysosome fuses with one autophagosome to form the secondary lysosome. The enzymes in the secondary lysosome are activated and digest the contents of autophagosome.10
 
iii. Removal of excess secretory products in the cells
Lysosomes in the cells of the secretory glands play an important role in the removal of excess secretory products by degrading the secretory granules.
 
iv. Secretory function – Secretory lysosomes
Recently, lysosomes having secretory function called secretory lysosomes are found in some of the cells particularly in the cells of immune system. The conventional lysosomes are modified into secretory lysosomes by combining with secretory granules (which contain the particular secretory product of the cell).
Examples of secretory lysosomes:
  1. Lysosomes in the cytotoxic T lymphocytes and natural killer (NK) cells, secrete perforin and granzymes which destroy both virus infected cells and tumor cells. Perforin is a pore-forming protein that initiates cell death. Granzymes which belong to the family of serine proteases (enzymes that dislodge the peptide ponds of the proteins) cause the cell death by apoptosis.
  2. Secretory lysosomes of melanocytes secrete melanin.
  3. Mast cells secrete serotonin by means of secretory lysosome. Serotonin is an inflammatory mediator.
 
■ 4. PEROXISOMES
Peroxisomes or microbodies are the membrane limited vesicles like the lysosomes. Unlike lysosomes, peroxisomes are pinched off from endoplasmic reticulum and not from the Golgi apparatus. Peroxisomes contain some oxidative enzymes such as catalase, urate oxidase and D-amino acid oxidase.
 
Functions of Peroxisomes
Peroxisomes:
  1. Degrade of toxic substances like hydrogen peroxide and other metabolic products by means of detoxification. A large number of peroxisomes are present in the cells of liver which is the major organ for detoxification. Hydrogen peroxide is formed from poisons or alcohol, which enter the cell. Whenever hydrogen peroxide is produced in the cell, the peroxisomes are ruptured and the oxidative enzymes are released. These oxidases destroy hydrogen peroxide and the enzymes, which are necessary for the production of hydrogen peroxide
  2. Form the major site of oxygen utilization in the cells
  3. Breakdown the excess fatty acids
  4. Accelerate gluconeogenesis from fats
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    FIGURE 1-6: Structure of mitochondrion
  5. Degrade purine to uric acid
  6. Participate in the formation of myelin and bile acids.
 
■ 5. CENTROSOME AND CENTRIOLES
The centrosome is the cellular organelle situated near the center of the cell close to the nucleus. It consists of two structures called centrioles. These structures are cylindrical in shape and are made up of proteins. Centrioles are responsible for the movement of chromosomes during cell division.
 
■ 6. SECRETORY VESICLES
The secretory vesicles are the organelles with limiting membrane and contain the secretory substances. These vesicles are formed in the endoplasmic reticulum, and are processed and packed in Golgi apparatus. The vesicles are present throughout the cytoplasm. When necessary, the secretory vesicles are ruptured and the secretory substances are released into the cytoplasm.
 
■ 7. MITOCHONDRION
The mitochondrion (pleural = mitochondria) is a rod or oval shaped structure with a diameter of 0.5 to 1 µ. It is a bilayered membranous organelle (Fig. 1-6). The outer membrane is smooth and encloses the contents of mitochondrion. It contains various enzymes such as acetyl-CoA synthetase and glycerolphosphate acetyltransferase.
The inner membrane is folded in the form of shelf like inward projections called cristae and it covers the inner matrix space. The cristae contain many enzymes and other protein molecules which are involved in respiration and synthesis of adenosine triphosphate (ATP). Because of these functions, the enzymes and other protein molecules in cristae are collectively known as respiratory chain or electron transport system.
The respiratory chain includes:
  1. Succinic dehydrogenase
  2. Dihydronicotinamide adenine dinucleotide (NADH) dehydrogenase
  3. Cytochrome oxidase
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  4. Cytochrome C
  5. ATP synthase.
The inner cavity of mitochondrion is filled with matrix which contains many enzymes. The mitochondria move freely in the cytoplasm of the cell and are capable of reproducing themselves. The mitochondria contain their own deoxyribonucleic acid (DNA) which is responsible for many enzymatic actions.
 
Functions of Mitochondrion
 
i. Production of energy
The mitochondrion is called the ‘power house of the cell’ because it produces the energy required for the cellular functions. The energy is produced during the oxidation of digested food particles like proteins, carbohydrates and lipids by the oxidative enzymes in cristae. During oxidation water and carbon dioxide are produced with release of energy. The released energy is stored in mitochondria and used later for synthesis of ATP.
 
ii. Synthesis of ATP
The components of respiratory chain in the mitochondrion are responsible for the synthesis of ATP by utilizing the energy through oxidative phosphorylation. The ATP molecules defuse throughout the cell from mitochondrion. Whenever energy is needed for cellular activity, the ATP molecules are broken down.
 
iii. Apoptosis
Cytochrome C and SMAC/diablo secreted in mitochondria are involved in apoptosis (see below).
 
■ 8. RIBOSOMES
The ribosomes are granular and small dot like structures with a diameter of 15 nm. Some ribosomes are attached to rough endoplasmic reticulum while others are present as free ribosomes in the cytoplasm. The ribosomes are made up of proteins (35%) and RNA (65%). The RNA present in ribosomes is called ribosomal RNA (rRNA).
 
Functions of Ribosomes
Ribosomes are called protein factories because of their role in the synthesis of proteins. Messenger RNA passes the genetic code for protein synthesis from nucleus to the ribosomes. The ribosomes, in turn arrange the amino acids into small units of proteins. The ribosomes attached with endoplasmic reticulum are involved in the synthesis of proteins like the enzymatic proteins, hormonal proteins, lysosomal proteins and the proteins of the cell membrane.
The free ribosomes are responsible for the synthesis of proteins of hemoglobin, peroxisome and mitochondria.
 
■ 9. CYTOSKELETON
The cytoskeleton of the cell is a complex network of structures of various sizes present throughout the cytoplasm. It determines the shape of the cell and gives support to the cell. It is also essential for the cellular movements and the response of the cell to external stimuli. It acts both as muscle and skeleton for the stability and movements of the cell. The cytoskeleton consists of three major protein components viz.
  1. Microtubules
  2. Intermediate filaments
  3. Microfilaments.
 
Microtubules
Microtubules are straight and hollow tubular structures without limiting membrane arranged in different bundles. Each tubule has a diameter of 20 to 30 nm. The length of the microtubules varies and it may be 1000 times more than the thickness.
Structurally, the microtubules are formed by bundles of globular protein called tubulin (Fig. 1-7 A). Tubulin has two subunits namely α and β subunits.
 
Functions of microtubules
Microtubules may function alone or join with other proteins to form more complex structures like cilia, flagella or centrioles and perform various functions.
Microtubules:
  1. Determine the shape of the cell
  2. Give structural strength to the cell
  3. Act like conveyer belts which allow the movement of granules, vesicles, protein molecules and some organelles like mitochondria to different parts of the cell
  4. Form the spindle fibers which separate the chromosomes during mitosis
  5. Are responsible for the movements of centrioles and the complex cellular structures like cilia.
 
Intermediate Filaments
The intermediate filaments form a network around the nucleus and extend to the periphery of the cell. Diameter of each filament is about 10 nm. The intermediate filaments are formed by rope like polymers which are made up of fibrous proteins (Fig. 1-7 B). These filaments are divided into five subclasses :
  1. Keratins – in epithelial cells
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    FIGURE 1-7: A = Microtubules. B = Intermediate filament. C = Microfilament of ectoplasm
  2. Glial filaments – in astrocytes
  3. Neurofilaments – in nerve cells
  4. Vimentin – in muscle fibers
  5. Desmin – in muscle fibers
The intermediate filaments help to maintain the shape of the cell. The adjacent cells are connected by intermediate filaments through desmosomes.
 
Microfilaments
Microfilaments are long and fine thread like structures with a diameter of about 3 to 6 nm. These filaments are made up of non tubular contractile proteins called actin and myosin. Actin is more abundant than myosin.
The microfilaments are present throughout the cytoplasm. The microfilaments present in ectoplasm contain only actin molecules and those present in endoplasm contain both actin and myosin molecules (Fig. 1-7 C).
 
Functions or microfilaments
Microfilaments:
  1. Give structural strength to the cell
  2. Provide resistance to the cell against the pulling forces
  3. Responsible for cellular movements like contraction, gliding and cytokinesis (partition of cytoplasm during cell division).
 
■ NUCLEUS
Nucleus is present in the cells, which divide and produce enzymes. The cells with nucleus are called eukaryotes and those without nucleus are known as prokaryotes (e.g. red blood cells). Prokaryotes do not divide or synthesize the enzymes.
Most of the cells are uninucleated, i.e. have only one nucleus. Few types of cells like skeletal muscle cells have many nuclei and are called the multinucleated cells. Generally the nucleus is located near the center of the cell. It is mostly spherical in shape. However, the shape and situation of nucleus vary in some cells.
 
■ STRUCTURE OF NUCLEUS
The nucleus is covered by a membrane called nuclear membrane. The nuclear membrane encloses the structures called nucleoplasm and nucleolus.
 
Nuclear Membrane
The nuclear membrane is double layered and porous in nature. This allows the nucleoplasm to communicate with the cytoplasm. The outer layer of nuclear membrane is continuous with the membrane of endoplasmic reticulum. The space between the two layers of nuclear membrane is continuous with the lumen of endoplasmic reticulum.
The pores of the membrane are guarded by protein molecules. The diameter of the pores is about 80 to 100 nm. However, it is decreased to about 7 to 9 nm because of the attachment of protein molecules with the periphery of the pores. The exchange of materials between nucleoplasm and cytoplasm occurs through these pores.
 
Nucleoplasm
It is a gel like ground substance of the nucleus. The nucleoplasm contains large quantities of the genetic material in the form of deoxyribonucleic acid (DNA) which forms the gene. The DNA made up of thread like material known as chromatin.
In the dividing cells, just before division, the chromatin becomes the rod shaped chromosome. There are 46 chromosomes in all the dividing cells of the body except gametes or sex cells, which contain only 23 chromosomes. The chromosomes carry the information about the hereditary characteristics and the individual characteristics of the person.13
 
Nucleoli
One or more nucleoli are present in each nucleus. The nucleolus contains ribonucleic acid (RNA) and some proteins, which are similar to those found in ribosomes. The RNA is synthesized by five different pairs of chromosomes and stored in the nucleolus. Later, it is condensed to form the subunits of ribosomes. All the subunits formed in the nucleolus are transported to cytoplasm through the pores of nuclear membrane. In the cytoplasm, these subunits fuse to form ribosomes which play an essential role in the formation of proteins.
 
■ FUNCTIONS OF NUCLEUS
  1. Control of all the activities of the cell
  2. Synthesis of RNA
  3. Formation of subunits of ribosomes
  4. Sending genetic instruction to the cytoplasm for protein synthesis through mRNA
  5. Control the cell division through genes
  6. Storage of hereditary information (in genes) and transformation of this information from one generation of the species to the next.
 
■ DNA
The genetic information of an organism is stored in genes of DNA. DNA forms the chemical basis of hereditary characters. It also forms the carrier for genetic information to the offspring. It contains the instruction for the synthesis of proteins in the ribosomes.
DNA is present in the nucleus and mitochondria of the cell. The DNA present in the nucleus is responsible for the formation of RNA. RNA regulates the synthesis of proteins by ribosomes.
 
■ STRUCTURE OF DNA
DNA is a double stranded complex nucleic acid. It is formed by deoxyribose, phosphoric acid and four types of bases. Each DNA molecule consists of two polynucleotide chains, which are twisted around one another in the form of a double helix. The two chains are formed by the sugar deoxyribose and phosphate. These two substances form the backbone of DNA molecule. Both chains of DNA are connected with each other by some organic bases (Fig. 1-8).
Each chain of DNA molecule consists of many nucleotides. Each nucleotide is formed by:
  1. Deoxyribose—sugar
  2. Phosphate
  3. One of the following organic (nitrogenous) bases:
    Purines
    – Adenine (A)
    – Guanine (G)
    Pyrimidines
    – Thymine (T)
    – Cytosine (C)
The strands of DNA are arranged in such a way that both are bound by specific pairs of bases. The adenine of one strand binds specifically with thymine of opposite strand. Similarly, the cytosine of one strand binds with guanine of the other strand.
DNA forms the component of chromosomes, which carries the genetic message.
 
■ GENE
A gene is a portion of DNA molecule that contains the message or code for the synthesis of a specific protein from amino acids. In the nucleotide of DNA, three of the successive base pairs are together called a triplet or codon. Each codon codes or forms code word (message) for one amino acid. There are 20 amino acids and there is separate code for each amino acid. For example, the triplet CCA is the code for glycine and GGC is the code for proline.
The arrangement or sequencing of different triplets in a portion of DNA is called gene. Thus, each gene forms the code word for a particular protein to be synthesized in ribosome (outside the nucleus) from amino acids.
 
■ RNA
The various functions coded in the genes are carried out in the cytoplasm of the cell by RNA. RNA is formed from DNA.
 
■ STRUCTURE OF RNA
Each RNA molecule consists of a single strand of polynucleotide unlike the double stranded DNA. Each nucleotide in RNA is formed by:
  1. Ribose – the sugar
  2. Phosphate
  3. One of the following organic bases:
    Purines
    – Adenine (A)
    – Guanine (G)
    Pyrimidines
    – Uracil (U)
    – Cytosine (C)
Uracil replaces the thymine of DNA and it has similar structure of thymine.
 
■ TYPES OF RNA
RNA is of three types. Each type of RNA plays a specific role in protein synthesis. The three types of RNA are:
 
1. Messenger RNA (mRNA)
It carries the genetic code of the amino acid sequence for synthesis of protein from the DNA to the cytoplasm.14
zoom view
FIGURE 1-8: (a) Double helical structure of DNA. (b) Magnified view of the components of DNA. A = Adenine. C = Cytocine. G= Guanine. P = Phosphate. S = Sugar. T = Thymine
 
2. Transfer RNA (tRNA)
This RNA is responsible for decoding the genetic message present in mRNA.
 
3. Ribosomal RNA (rRNA)
It is present within the ribosome and forms a part of the structure of ribosome. It is responsible for the assembly of protein from amino acids in the ribosome.
 
■ TRANSCRIPTION AND TRANSLATION
 
■ TRANSCRIPTION OF GENETIC CODE
The word transcription means copying. It indicates the copying of genetic code from DNA to RNA. The proteins are synthesized in the ribosomes which are present in the cytoplasm. However, the synthesis of different proteins depends upon the message (sequence of codon) encoded in the genes of the DNA which is present in the nucleus. Since, DNA is a macromolecule, it cannot enter the cytoplasm through the pores of the nuclear membrane. But, the message from DNA must be sent to ribosome. So, the gene has to be transcribed (copied) into mRNA which is developed from DNA.
Thus, the first stage in the protein synthesis is transcription of genetic code, which occurs within the nucleus. It involves the formation of mRNA and simultaneous copying or transfer of message from DNA to mRNA. The mRNA enters the cytoplasm from the nucleus and activates the ribosome resulting in protein synthesis. 15The formation of mRNA from DNA is facilitated by the enzyme RNA polymerase.
 
■ TRANSLATION
Translation is the process by which protein synthesis occurs in the ribosome of the cell under the direction of genetic instruction carried by mRNA from DNA. This involves the role of other two types of RNA namely tRNA and rRNA.
The mRNA moves out of nucleus into the cytoplasm. Now, the group of ribosomes called polysome gets attached to mRNA. The sequence of codons in mRNA are exposed and recognized by the complementary sequence of base in tRNA. The complementary sequence of base is called anticodon. According to the sequence of bases in anticodon, different amino acids are transported from the cytoplasm into the ribosome by tRNA that acts as a carrier. With the help of rRNA, the protein molecules are assembled from amino acids. The protein synthesis occurs in the ribosomes which are attached to rough endoplasmic reticulum.
 
■ GROWTH FACTORS
Growth factors are proteins which act as cell signaling molecules like cytokines and hormones. These factors bind with specific surface receptors of the target cell and activate proliferation, differentiation and / or maturation of these cells.
Often the term growth factor is interchangeably used with the term cytokine. But growth factors are distinct from cytokines. Growth factors act on the cells of the growing tissues. Where as the cytokines are concerned with the cells of immune system and hemopoietic cells.
Many growth factors are identified. The known growth factors are:
  1. Platelet derived growth factor – PDGF (Chapter 18)
  2. Colony stimulating factors CSF(Chapter 16)
  3. Nerve growth factors – NGF (Chapter 134)
  4. Neurotropins (Chapter 134)
  5. Erythropoietin (Chapter 10)
  6. Thrombopoietin (Chapter 18)
  7. Insulin like growth factors – IGF (Chapter 66)
  8. Epidermal growth factor – present in keratinocytes and fibroblasts. It inhibits growth of hair follicles and cancer cells
  9. Basic fibroblast growth factor – present in blood vessels. It is concerned with formation of new blood vessels
  10. Myostatin – present in skeletal muscle fibers. It controls skeletal muscle growth
  11. Transforming growth factors (TGF) – present in transforming cells (cells undergoing differentiation) and in large quantities in tumors and cancerous tissue. TGF is of two types:
    1. TGF-α secreted in brain, keratinocytes and macrophages. It is concerned with growth of epithelial cells and wound heeling.
    2. TGF-β secreted by hepatic cells, T cells, B cells, macrophages and mast cells. When the liver attains the maximum size in adults it controls liver growth by inhibiting proliferation of hepatic cells. It also causes immunosuppression.
 
■ CEL DEATH
The cell death occurs by two distinct processes:
  1. Necrosis
  2. Apoptosis.
 
■ NECROSIS
Necrosis (means ‘dead’ in Greek) is the uncontrolled and unprogrammed death of cells due to unexpected and accidental damage. It is also called ‘cell murder’ because the cell is killed by extracellular or external events. After necrosis, the harmful chemical substances released from the dead cells cause damage and inflammation of neighboring tissues.
 
Causes for Necrosis
Common causes of necrosis are injury, infection, inflammation, infarction and cancer. Necrosis is induced by both physical and chemical events such as heat, radiation, trauma, hypoxia due to lack of blood flow, and exposure to toxins.
 
Necrotic Process
Necrotic process results in lethal disruption of cell structure and activity. The cell undergoes a series of characteristic changes during necrotic process viz.
  1. Cell swells causing damage of the cell membrane and appearance of many holes in the membrane
  2. The intracellular contents leak out into the surrounding environment
  3. The intracellular environment is altered
  4. Simultaneously, large amount of calcium ions are released by the damaged mitochondria and other organelles
  5. Organization and activities of proteins in the intracellular components are drastically affected by the presence of calcium ions
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  6. Calcium ions also induce release of toxic materials that activate the lysosomal enzymes
  7. Lysosomal enzymes cause degradation of cellular components and, the cell is totally disassembled resulting in death
  8. The products broken down from the dissembled cell are ingested by neighboring cells.
 
Reaction of Neighboring Tissues After Necrosis
The tissues surrounding the necrotic cells react to the breakdown products of the dead cells particularly the derivatives of membrane phospholipids like the arachidonic acid. Along with other materials, this free fatty acid causes the following inflammatory reactions in the surrounding tissues:
  1. Dilatation of capillaries in the region and there by increasing local blood flow
  2. Increase in the temperature leading to reddening of the tissues
  3. Release of histamine from these tissues which induces pain in the affected area
  4. Migration of leukocytes and macrophages from blood to the affected area because of increased capillary permeability
  5. Movement of water from blood into the tissues causing local edema
  6. Engulfing and digestion of cellular debris and foreign materials like bacteria by the leukocytes and macrophages
  7. Activation of immune system resulting in the removal of foreign materials
  8. Formation of pus by the dead leukocytes during this process
  9. Finally, tissue growth in the area and wound healing.
 
■ APOPTOSIS
Apoptosis is defined as the programmed cell death under genetic control. Originally apoptosis (means ‘falling leaves’ in Greek) refers to the process by which the leaves fall from trees in autumn. It is also called ‘cell suicide’ since the genes of the cell play a major role in the death.
This type of programmed cell death is a normal phenomenon and it is essential for normal development of the body. In contrast to necrosis, apoptosis usually does not elicit inflammatory reactions in the neighboring tissues.
 
Functional Significance of Apoptosis
The main function of apoptosis is to remove unwanted cells without causing any stress or damage to the neighboring cells. The functional significance of apoptosis:
  1. Plays a vital role in cellular homeostasis. About 10 million cells are produced everyday in human body by mitosis. An equal number of cells die by apoptosis. This helps in cellular homeostasis
  2. Useful for removal of a cell that is damaged by a virus or a toxin beyond repair
  3. An essential event during the development and in adult stage.
Examples:
  1. A large number of neurons are produced during the development of central nervous system. But up to 50% of the neurons are removed by apoptosis during the formation of synapses between neurons
  2. Apoptosis is responsible for the removal of tissues of webs between fingers and toes during developmental stage in fetus
  3. It is necessary for regression and disappearance of duct systems during sex differentiation in fetus (Chapter 74)
  4. The cell that looses the contact with neighboring cells or basal lamina in the epithelial tissue dies by apoptosis. This is essential for the death of old enterocytes shed into the lumen of intestinal glands (Chapter 41)
  5. It plays an important role in the cyclic sloughing of the inner layer of endometrium resulting in menstruation (Chapter 80)
  6. Apoptosis removes the auto-aggressive T cells and prevents autoimmune diseases.
 
Activation of Apoptosis
Apoptosis is activated by either withdrawal of positive signals (survival factors) or arrival of negative signals.
 
Withdrawal of positive signals
Positive signals are the signals which are necessary for the long time survival of most of the cells. The absence or withdrawal of positive signals activates apoptosis.
The positive signals are continuously produced by other cells or some chemical stimulants.
Best examples of chemical stimulants are:
  1. Nerve growth factors (for neurons)
  2. Interleukin-2 (for cells like lymphocytes).
 
Arrival of negative signals
Negative signals are the external or internal stimuli which initiate apoptosis. The negative signals are produced during various events like:
  1. Normal developmental procedures
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  2. Cellular stress
  3. Increase in the concentration of intracellular oxidants
  4. Viral infection
  5. Damage of DNA
  6. Exposure to agents like chemotherapeutic drugs, X-rays, ultraviolet light, and the death receptor ligands.
 
Death receptor ligands and death receptors
Death receptor ligands are the substances which bind with specific cell membrane receptors and initiate the process of apoptosis. The common death receptor ligands are tumor necrosis factors (TNF-α, TNF-β) and Fas ligand (which binds to the receptor called Fas).
The cell membrane receptors which receive the death receptor ligands are known as death receptors. Well characterized death receptors are TNF receptor-1 (TNFR1) and TNF-related inducing ligand (TRAIL) receptors called DR4 and DR5.
 
Role of mitochondria in apoptosis
The external or internal stimuli initiate apoptosis by activating the proteases called caspases (cysteinyl-dependant aspartate specific proteases). Normally, caspases are suppressed by the inhibitor protein called apoptosis inhibiting factor (AIF).
When the cells receive the apoptotic stimulus, mitochondria releases two protein materials. The first one is Cytochrome C and the second protein is called second mitochondria-derived activator of caspases (SMAC) or its homologue diablo.
SMAC/diablo inactivates AIF so that the inhibitor is inhibited. During this process SMAC/diablo and AIF aggregate to form apoptosome which activates caspases. Cytochrome C also facilitates caspase activation.
 
Apoptotic Process
Cell shows sequence of characteristic morphological changes during apoptosis viz.:
  1. Activated caspases digest the proteins of cytoskeleton and the cell shrinks and becomes round
  2. Because of shrinkage, the cell losses the contact with neighboring cells or surrounding matrix
  3. Chromatin in the nucleus undergoes degradation and condensation
  4. The nuclear membrane becomes discontinuous and the DNA inside nucleus is cleaved into small fragments
  5. Following the degradation of DNA, the nucleus breaks into many discrete nucleosomal units which are also called chromatin bodies
  6. The cell membrane breaks and shows bubbled appearance
  7. Finally, the cell breaks off into several fragments containing intracellular materials including chromatin bodies and organelles of the cell. Such cellular fragments are called vesicles or apoptotic bodies
  8. The apoptotic bodies are engulfed by phagocytes and dendritic cells.
 
Abnormal Apoptosis
Apoptosis within normal limits is beneficial for the body. However, too much or too little apoptosis leads to abnormal conditions.
Common abnormalities due to too much apoptosis:
  1. Ischemic related injuries
  2. Autoimmune diseases like
    1. Hemolytic anemia
    2. Thrombocytopenia
    3. Acquired immunodeficiency syndrome (AIDS)
  3. Neurodegenerative diseases like Alzheimer's disease.
Common abnormalities due to too little apoptosis:
  1. Cancer
  2. Autoimmune lymphoproliferative syndrome (ALPS).