Cell Components and Functions

1. Cell Cell interactions and typical signaling events

  • All cells have surface markers that enable other cells to identify them and these surface markers are either a protein or a glycolipid. Once the appropriate cell is identified in any given chemical signaling event, other cells will "communicate" with the cell through a process called cell signaling. All signaling consists of a chemical signal that is being passed between cells and a receptor that recieves this chemical signal. There are cell surface receptors (including g-proteins, enzymic, and chemically gated ion channels) with a specific 3-D shape that allows only certain ligands (the messenger from the cell sending chemical signal) to bind based on the ligand's shape. There are also intercelluler receptors that are found within the cell in the cytoplasm or nucleus that are accessed by a ligand that is lipid soluble or small enough to be able to cross the cell membrane in order to bind with the appropriate receptor. When the ligand binds with the cell surface or intercellular receptor it causes a change in shape of the receiving cell's receptor causing a cellular response inside the cell. There are four types of cell signaling that may be utilized including direct contact, paracrine signaling, endocrine signaling and synaptic signaling.
  • Direct contact signaling is achieved through forming cell junctions, which include tight junctions, communicating junctions and gap junctions. Tight junctions are formed with the cells being very close together and a wall like barrier is formed that makes it difficult for anything to enter or exit. Communicating junctions occur when the cytoplasm of adjacent cells link together to allow small molecules or ions to pass between the cells. Gap junctions occur when there is a large enough "gap" in the cytoplasm for simple sugars and amino acids to pass between cells. A gap junction is usually not big enough for larger molecules like protiens to pass through.
  • Paracrine signaling (always indicates local effects) affects other cells in the immediate area (of the cell sending out the signal) and therby has a local effect only. The effect only extends to cells in the immediate area due to either the signal/ligand being taken up by cells, destroyed by extracellular fluid or being quickly removed from the extracellular fluid by any other mechanism.
  • Endocrine signaling (indicates wide spread effects) affects cells through out the body as the signal is able to travel widely. If a signal is considered to be an endocrine signal then it is also referred to as a hormone.
  • Synaptic signaling involves the release of neurotransmitters into a synapse formed between two cells. The postsynaptic cell has receptors on it's surface to receive the neurotransmitter that was released and traveling within the synapse. The message is then relayed in this manner from cell to cell if necessary.

2. How is the cell membrane renewed?

The cell membrane is renewed through a few different routes:

  • The Golgi Apparatus modifies products from the Endoplasmic Reticulum, producing a large variety of oligosaccharides. It also manufactures certain macromolecules by itself (many polysaccharides secreted by cells are Golgi products). Golgi products that will be secreted depart from the trans face of the Golgi inside transport vesicles that eventually fuse with the plasma membrane. Before a Golgi stack dispatches its products by budding vesicles from the trans face, it sorts the products and targets them for various parts of the cell. Molecular identification tag, such as phosphate groups that have been added to the Golgi products, aid in sorting. Transport vesicles budded from the Golgi may also have external molecules on their membranes that recognize “docking sites” on the surface of specific organelles or on the plasma membrane.
  • The Endoplasmic Reticulum aids in insertion of proteins into membrane. An N-terminus signal sequence of amino acids directs proteins to the ER, which inserts the proteins into a lipid bilayer. Once inserted, the proteins are then transported to their final destination in vesicles, where the vesicle fuses with the target membrane.
  • Phospholipid molecules can also be exchanged between intracellular and extracellular portions of the lipid bilayer.
  • This set up allows for the cell membrane, and consequently the cell as a whole, to have some flexibility to respond to changes in the environment. Allows the cell to: receive signals, cell-to-cell identification, cell-to-cell communication, cell-to-cell interaction in immune function (lymphocyte homing), and cell adhesion.

3. Transcription and the major molecules involved
Transcription is the synthesis of mRNA from a DNA template.
Transcription is the first step leading to gene expression. Gene expression is the most fundemental level where the genotype gives rise to the organism's phenotype.

The process of transcription involves 3 main events: Initiation, Elongation, and Termination.
The properties involved in transcription include nucleotides (A, G, T, C), transcription factors, and RNA polymerase.
-During the Elongation process of transcription, the nucleotides are copied and paired (i.e. A-T, C-G) except in the mRNA copy the Thymine's are replaced with Uracil.
-Transcription factors help the RNA polymerase to bind during the initiation phase.
-Once Elongation has begun, the RNA polymerase copies the DNA sequence through base pairing, which was described above.
-Termination occurs when the RNA polymerase releases and the the DNA strand has been completely copied.

**mRNA will then be used to create the protein via translation.

4. Translation and the major molecules involved

*Translation is the synthesis of proteins by decoding messenger RNA (mRNA) produced during transcription.
*Translation occurs in the cytoplasm where ribosomes are found
*The process of making a new protein is carried out by the ribosome.
*Translation occurs in three phases
1. Initiation: A ribosome attaches to the mRNA and starts the decoding process at the first codon.
2. Elongation: Transfer RNA (tRNA) brings the correct amino acid to each codon according to what is specified by the mRNA strand. The amino acids are attached together in the order specified by the mRNA to form a new protein.
3. Termination: The synthesis of the polypeptide chain is ended when the ribosome reads the last mRNA codon (also known as the stop codon), and the protein is released.

5. Explain how a large number of proteins are synthesized from relatively fewer genes

  • There are approximately 100,000 known proteins which differ in sequence but only around 30,000 genes in the human genome. Therefore, single genes are able to code for multiple proteins.
  • This occurs through a process known as alternative splicing. This happens after transcription, before translation. The pre-mRNA transcribed from one gene can lead to a variety of mature mRNA molecules that are synthesized into multiple different proteins.
  • The pre-mRNA is composed of introns and exons. In general, the introns are designed to be removed during splicing and the exons are destined to remain within the mRNA to code for the protein sequence. However this does not always happen. During splicing, the exons are either removed or retained in the mRNA in different combinations. There are several types of common gene splicing patterns including exon skipping, intron retention, and alternative splice sites. For example, in exon skipping an exon may remain in the mRNA under some conditions and be omitted from the mRNA in others. The splicing is regulated by trans-acting proteins that bind to cis-acting sites on the pre-mRNA. These different combinations then become mature mRNA and move on to be translated and synthesized into proteins.
  • Alternative splicing leads to the synthesis of alternate proteins that play a role in human physiology and disease. It is thought that a number of human genetic disorders arise from spliced variants.

6. Innate Immune System and cellular components

  • The innate immune system is different from the adaptive immune system (see below), as its reponse is non-specific - the system reponsds to pathogens in a generic way; exposure leads to immediate maximal response; there is no immunological memory; and it is found in nearly all forms of life.
  • The innate response is generally triggered when microbes are identified by pattern recognition receptors.
  • Leukocytes (WBCs) are the main cellular components acting within the innate immune system.
  • The innate leukocytes include the phagocytes: macrophages (rid the body of worn-out cells and other debris), neutrophils (migrate toward the site of inflammation to invade pathogens and most abundant type of phagocyte), dendritic cells (in skin, nose, lungs, stomach, intestines), mast cells (regulate the inflammatory response), basophils and eosinophils (secrete chemical mediators involved in defending against parasites/play role in allergic reactions), natural killer (NK) cells (attack and destroy tumor cells).

Murphy EA, Davis JM, Carmichael MD, Gangemi JD, Ghaffar A, Mayer EP. Exercise stress increases susceptibility to influenza infection. Brain, Behavior and Immunity (2008) 22:1152-1155.

Research is continually being done to investigate the effects of exercise on susceptibility to illness. Most studies have concentrated on strenuous exercise after exposure to flu. In this study, the researchers looked at the effect of 3 days of strenuous exercise followed by exposure to the H1N1 flu virus in mice. The critical question looked to find what the effects of 3 consecutive days of prolonged severe exercise on susceptibility (morbidity – time to sickness, symptom severity, mortality – time to death) to influenza virus infection in mice.
Methods: 4 week-old male mice were used. Experiments were performed at the beginning of the active dark cycle. Mice were kept on 12:12 light-dark cycle. Exercise mice acclimated to TM for 20min/day for 3 days prior to exhaustive bouts. On day 3, mice exposed to either control or exercise treatment, then returned to cages. Exercise bouts consisted of 3 consecutive days of running on TM at 70-80% estimated VO2 max (based on a study by Taylor, 1987) for about 2 hours. Mice removed when volitional fatigue was reached (could not keep pace despite 1 min of hand prodding). After 15 min,(wait for breathing to be back to normal) all were lightly anesthetized and inoculated with flu virus (H1N1). This same dose yielded 50% mortality rate among control mice in preliminary experiments. All mice returned to cages(5 per cage) and monitored by a blinded investigator daily for 21 days for signs of morbidity, sx severity, and mortality.
Outcome measures were body weights taken daily (as a more objective measure of sickness); morbidity(any of the symptoms shown), symptom severity and mortality. Symptom severitywas rated 1 to 3 on severity, and included: ruffled fur, redness around the eyes/nose/mouth (weighted less, days 4-5), hunched back pose, altered respiration on day 5 and 6, and unresponsiveness on day 6.
Results: There was a significant increase in morbidity (time to sickness) with exercising mice (compared to resting controls) following receipt of flu virus dose (mean time for exercising mice was 7.5 days vs 11 days for controls). There was a 90% morbidity rate for exercise mice vs. 72% for control mice. Exercise mice had significantly higher symptom severity than control mice on days 6 and 7. Body weight was significantly decreased in both groups on days 4-7. There was a significantly greater percentage of decrease in body weight in exercise mice vs the control group. Exercise mice has significantly greater mortality, which a mean time to death of 9.4 days, where the control group had 12.9 days until death. Overall mortality was 85% in the exercise group compared to 66% in controls.
Relevance of the findings: This is evidence (at least in animal models) that stressful exercise can increase the risk of respiratory infection, and the flu virus is one of the most common and serious respiratory infections in humans. Perhaps high risk individuals should avoid exhaustive exercise, especially on consecutive days. Perhaps we should warn our athletes to get a flu shot, handwashing, etc for extra precautions since they are more susceptible. We should have monitoring systems in effect for athletes who are getting sick so they can get treatment more quickly.
Limitations/flaws include small sample sizes, lack of/unknown generalizability to human subjects, animals did not exercise prior to 3 days 20 min each, then 3 exhaustive days, Reliability/validity of using those outcome measures, and lack of consistentcy from one virus to another.

7. Adaptive Immune System and cellular components
*The response of adaptive immunity consists of antigen specific reactions. The adaptive response is precise and may take several days or weeks to develop (in contrast to the innate response which is rapid but due to lack of specificity sometimes damages normal tissues). The adaptive response has memory so that following exposures to the same antigen will have a more vigorous and faster response.
*Consists of lymphocytes: B-cells and T-cells. Bone marrow produces both and the T-cells develop in the thymus.
~B-cells-produce antibodies. Each cell is programed to produce one antibody and recognize a single antigen.
~T-cells
1. Helper T cells (CD4)- produce cytokines. They recognize foreign antigen and activate other parts of the cell-mediated immune
response. They play a major role in the activation of B cells.
2.Cytotoxic T cells (CD8)- destroy infected cells
*High specificity- there are huge numbers (108 T-cell receptors and 10 10 antibody specificities) ready to respond to an antigen but only a few of the lymphocytes are able to respond to a particular antigen.
*Creation of new clones of T & B cells occurs throughout life.

8. Mitochondria
*Mitochondria have a complex structure which aids in its function.
-The outer membrane contains the organelle, and is a phospholipid bilayer. Because of protein structures called porons, this membrane
is permeable to small proteins.
-The inner membrane is permeable to water, carbon dioxide, and oxygen. It contains the structures involved in the electron transport
system and ATP synthesis. The inner membrane contains many folds called cristae, which increases surface area and allows more work to
be performed in the inner membrane.
-The intermembrane space plays a role in oxidative phosphorylation.
-The fluid inside of the mitochondria is called the matrix, and it contains ribosomes and DNA.
*The main function of mitochondria is to convert organic materials into ATP (they are the powerhouse of the cell!)
-Without oxygen, cells produce ATP through glycolysis.
-Glycolysis produces pyruvate and NADH, which are then metabolized.
-The citric acid cycle is anaerobic, and takes place within the matrix.
-Active transport is used to transport pyruvate across the inner mitochondrial membrane into the matrix. Inside the matrix, it is combined
with coenzyme A to form acetyl CoA.
-Acetyl CoA is fed into the citric acid cycle, which creates 3 molecules of NADH and 1 molecule of FADH2. These are used in oxidative
phosphorylation, which utilizes oxygen.
-The energy from NADH and FADH2 is transferred to oxygen via the electron transfer chain. A protein pump transfers protons against the
gradient into the intermembrane space.
-As the proton concentration increases in the intermembrane space, a concentration gradient is built. These protons leave through the ATP
synthase complex, allowing the ATP synthase complex to make ATP from ADP and inorganic phosphate (called chemiosmosis).
-The presence of oxygen and the citric acid cycle allows the pyruvate to be broken down into carbon dioxide and water to produce 24 -28
ATP.

9. Golgi System
- Flattened membranous sacs that function as the "shipping and receiving" area of the cell.
- Receives material (like glycoproteins) from the ER in transport vesicles.
- This material is then modified as needed, sorted, and "shipped" out in target vesicles to the area of the cell that needs the material.
- The golgi can also manufacture some materials including pectin and non-cellulose polysaccharides.

10. Rough endoplasmic Reticulum
*The rough endoplasmic reticulum is part of a network of membranes which are consistent with the nuclear membrane of the cell.
*The Rough ER contains ribosomes which aid in the production of glycoproteins.
*Also functions as a producer of new membrane material that can be transported throughout the cell in order to prepare the cell for division.

  • Sends glycoproteins and other products it produces to the Golgi Complex so that they may be chemically modified.

11. Smooth Endoplasmic Reticulum

  • smooth ER has no ribosomes, it curves through the cytoplams like connecting pipes, smooth apperance
  • 3 important roles:
    • chemicaly modifying small molecules taken in by the cell, especially drugs and pesticides
    • site for hydrolysis of glycogen in animal cells
    • site of synthesis of lipids and steroids
  • cells that synthesize a lot of protein for export (i.e. glandular cells for digeive enzymes) have LOTS of ER, some proteins that are syntesized in the rough ER re chemically modifie in the smooth ER
  • liver cells have aundant smooth ER, inactivate certain drugs and toxic metabolic wastes
  • smooth ER sequesters calcium from the cytosol, the release and reptake of calcium from the ER is involved in things like muscle contraction (i.e. sarcoplasmic reticulum in skeletal muscle cells is a type of smooth ER)
  • references:
    • Starr and Taggart. Biology: The Unity and Diversity of Life. 10th ed. Thomson: 2004.
    • Sadava, Heller, Orians, et al. Life: The Science of Biology. 8th ed. Sinauer Assoc., Inc.: 2008.
    • Alberts, Bray, Hopkins, et al. Essential Cell Biology. 2nd ed. Garland Science: 2004.

12. Lysosomes
-Lysosomes act as the digestive system of the cell. They contain enzymes that break down fats, carbohydrates, proteins, etc. They also digest foreign bacteria or other substances outside the cell and ingest obsolete cells. The rough ER makes these enzymes and the lysososomal membrane, which are then taken to the Golgi apparatus for processing. They are formed by fusing transport vesicles with endosomes through endocytosis.
-Lysosomes used to be called "suicide sacs" because they were thought to be a part of the process of apoptosis; however, they do not decide which materials to degrade, and so they should not be thought of as "self-destructing".
-Without lysosomes, cells would not be able to break down carbohydrates, proteins, fats, etc. necessary for proper cell function. In lysosomal storage disorders, such as Tay-Sachs disease, the lysosomes lack certain enzymes to break down fatty acids. So fatty acids build up in nerve cells of the brain, destroying the cell and ultimately leading to death before the age of 4 years.
References:
*Campbell NA, Reece JB. A tour of the cell. In: Biology, Sixth edition. San Francisco, CA: Benjamin Cummings; 2002: 121-122.
*Lysosomes-a 'new look' from new research. The British Society for Cell Biology. Available at: www.bscb.org/printable.php?url=softcell/lysosome Accessed January 8, 2010.
*Lysosomes. National Institute of Health. Available at: www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=cooper&part Accessed January 8, 2010.

13. Transcription Factors
14. Genes, chromosomes, DNA
DNA:

  • Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all living organisms. DNA can be compared to a set of blueprints or a code that contains the instructions needed to construct the components of the cell such as proteins and RNA molecules. The information in DNA is stored as a code made up of four chemical bases; adenine (A), guanine (G), cytosine (C), and thymine (T). The sequence of these bases determines the information available for building and maintain an organism. The bases pair up and combine with a sugar and phosphate to form nucleotides. Nucleotides are arranged in two long strands that form a spiral called a double helix.

*DNA can replicate and each strand of the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.

Gene:

  • A gene is made up of DNA and is the basic physical and functional unit of heredity. Genes vary in size from a few hundred DNA bases to more than 2 million bases. Every person has 2 copies of each gene, one inherited from each parent. All organisms have many genes corresponding to many different biological traits, such as eye color and blood type.

*A gene mutation occurs when there is a permanent change in the DNA sequence of a gene. Mutations prevent one or more proteins from working properly, which can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder. As physical therapists we will work with many patients with genetic disorders for example: cystic fibrosis and hunington’s disease.

Chromosomes:

  • DNA molecules are packaged into thread-like structures called chromosomes. In every cell of our body, there are 20,000 to 25,000 genes that are located on 46 chromosomes. These 46 chromosomes occur as 23 pairs, one of each pair from our mother and one from our father. The last pair are called sex chromosomes labeled X or Y, with females having 2 X chromosomes, and males having an X and a Y chromosome.

*Chromosome mutations include chromosome deletions, duplications, inversions, and translocations, causing changes in the individuals health and development. Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 21st chromosome, known as trisomy 21.

15. Nucleus - The nucleus is a large, membrane-bound, central control center of the cell that contains the genetic material and controls all cellular activity (metabolism, growth, and cellular reproduction) by regulating gene expression as the transcription process occurs within the nucleus. As mitosis occurs, the nucleus is divided into two identical parts prior to cellular division.

  • Subnuclear body - nucleolus: responsible for synthesizing rRNA and ribosome assembly which are necessary components for the translation process to occur within the cytoplasm.
  • Large molecules (like proteins) are transported across the nucleus membrane by means of active transport.

16. Autonomic Nervous System (ANS) - Allows for regulation of the internal environment by innervating smooth and cardiac muscles, and organs of the gastrointestinal, cardiovascular, excretory, and endocrine systems. The ANS acts via Motor (Efferent) pathways as part of the Peripheral Nervous system. Their are two divisions of the Autonomic Nervous System, the Sympathetic Division and the Parasympathetic Division.

The Sympathetic Division - "Fight or Flight" responses. Activating the sympathetic division causes arousal and energy generation. Examples include:
- Increased Heart rate and vasodilation of coronary arteries (allows for larger amounts of blood to reach skeletal muscles)
- Increased glucose production
- Dilation of the bronchi of the lungs to facilitate increased gas exchange
- Inhibition of digestion (Diverts blood flow from GI tract, constricts all sphincter muscles of GI tract, inhibits peristalsis)
- Adrenaline secretion
- Dilation of pupils
- Orgasm

The Parasympathetic Division - "Rest and Digest" responses. Activating the Parasympathetic division causes a calming reaction and emphasis on self-maintenance functions. Examples include:
- Decreased Heart Rate
- Increased Energy/Nutrient Storage
- Bronchi Constriction (due to decreased oxygen demand)
- Stimulation of Organs to Facilitate Digestion (Increases blood flow to GI tract, acceleration of peristalsis)
- Constricts pupils
- Stimulates sexual arousal

17. Cytoskeleton is composed of three main elements present in all cells; mircofilaments, mircotubles, and intermediate filaments. It is both a muscle and a skeleton, and is responsible for cell movement, cytokinesis, and the organization of the organelles within the cell. The cytoskeleton is contained in the cytoplasm that is made out of protein and interacts extensively and intimately with cellular membranes.
*Microfilaments are primarily composed of actin, a fine thread-like protein fiber. Another protein, myosin, is another protein in association with actin that is responsible for muscle contraction. Microfilaments are found predominately under the cell membrane, and are responsible for resisting tension and maintaining cellular shape, forming cytoplasmatic protuberances, and participation in some cell-to-cell or cell-to-matrix junctions. In association with these latter roles, microfilaments are essential to transduction. Other cellular movements carried out include: gliding, contraction, and cytokinesis.
*Microtubules are cylindrical tubes that act as a support structure to determine cell shape, and provide a path for cell organelles and vesicles to move on (intracellular transport, eg. Mitochondria). They are composed of subunits of the protein tubulin. Microtubules also form the spindle fibers for separating chromosomes during mitosis. When arranged in patterns inside flagella and cilia, they are used for locomotion.
***Intermediate filaments provide tensile strength for the cell like cables, more strongly bound than actin filaments, resisting compression better. They also are important for cytokinesis (cleavage furrow) and along with myosin, muscle contraction. The interactions with actin/myosin help produce cytoplasmic streaming in most cells. They participate in some cell-cell and cell-matrix junctions. Different intermediate filaments are: vimentins (structural support of many cells), keratin (found in skin cells, hair and nails), and lamin(structural support to the nuclear envelope).
In summary the cytoskeleton provides a support structure for cells, protein for muscle contractions, and acts as a "track" for cell movement some examples are: Vesicle movement between organelles and the cell surface, Cytoplasmic streaming, Movement of pigment vesicles for protective coloration
Discharge of vesicle content for water regulation in protozoa, Cell division—cytokinesis, and Movement of chromosomes during mitosis and meiosis

18. Ribosomes
*Small, dense granules that are found in all cells, but their number varies depending on the type of cell and its activities.
*Each ribosome consists of approximately 60% RNA and 40% protein.
*Ribosomes are organelles that are intracellular factories that manufacture proteins using information from DNA.
*During protein synthesis, the ribosome consists of two subunits that interlock. Once protein synthesis is complete, these subunits separate.
*There are two major types of ribosomes –
A. Free Ribosomes: scattered throughout the cytoplasm, manufacture proteins that enter the cytosol.
B. Fixed Ribosomes: attached to the rough endoplasmic reticulum (RER), they synthesize proteins using instructions provided by a
strand of RNA. These manufactured proteins enter the lumen of the ER where they are modified and packaged for export (they are
packaged into transport vesicles which are delivered to the Golgi apparatus).
*Ribosomes can make a protein chain of 400 amino acids in about 20 seconds.
*They allow for protein synthesis and proteins are required for enzymatic activity, cellular structures and functioning, metabolic activity, and are essential for life to occur. Even viruses are composed of proteins.

19. Cell membrane

The Cell Membrane is mostly comprised of lipids, proteins and carbohydrates. The proportion of these types varies on the cell type, however all cells are comrpised mostly of lipids. The Structure of the cell membrane is a phospholipid bilayer with proteins embedded into the bilayer that is semi permeable. The membrane separates the cytoplasm from the extracellular matrix. The Bilayer consists of a phosphate head with a fatty acid chain attached. The polar heads of the bilayer are known as "hydrophilic" meaning they like water and face both the intra and extracelluar matrix aqueous solution. The fatty acid tails are non polar and are hydrophobic meaning they do not like water solutions and thus are protected from the outside environment by the polar heads. The proteins embedded into the bilayer are responsible for controlling the entry and exit of ions( Sodium, potassium and calcium) into and out of the cell. Most proteins have hydrophilic and hydrophobic components that can penetrate the cell membrane. Molecules transfer in and out of the cell via passive and active transport. Passive transport is the diffusion across the membrane secondary to the concentration gradient (high to low). Passive transport can be broken down into simple and facilitated difffusion where simple is based on the size of the molecule and lipid solubility and facilitatied is when the help of transport proteins are needed for polar charged molecules to cross. Active transport involves the movement of molecules agains the concentration gradient from low to high concentrations and requires the utilization of ATP as the energy source to complete the action. There are four main types of proteins: transport, recognition, receptor and cell adhesion. Small neutral charged molecules can cross the membrane easier than large charged molecules.

References: Russell, Wolfe, Hertz, Starr. Biology; the dynamic science. Thompson Brooks/Cole: 2008
Sadava, Heller, Orians, Purces. Life the science of biology. 8th ed. Sinauer Associates: 2008

20. Mitochondrial DNA

Mitochondria have their own DNA because billions of years ago eukaryotic cells could not produce their own energy, but bacterial cells could. So, these eukaryotic cells engulfed the bacterial cells, and these bacteria evolved into mitochondria. This is called endosymbiotic theory. It explains why mitochondria divide like bacteria (using fission-like processes) rather than via mitosis.

The human mitochondrial genome, which is separate from the genome found in the cell nucleus, contains 16,569 nucleotide pairs that encode 37 genes. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation, which is the process of using oxygen and simple sugars to make ATP. These enzymes are essential to oxidative phosphorylation. Thus, the cell cannot produce ATP without the mitochondria and its DNA. The rest of the genes in the mitochondrial genome provide instructions for making tRNA and rRNA (ribosomal RNA) that help assemble amino acids.

Mitochondria have their own DNA and RNA and a translation and transcription system that includes ribosomes, so mitochondria can synthesize their own proteins. Mitochondria grow and divide when there are increased energy needs, like when muscles repeatedly contract.

References

Alberts B, Bray D, Hopkin K, Johnson A, et al. Essential cell biology. 2nd Ed. Garland Science; New York: 2004.

Genetics Home Reference. Bethesda, MD: National Institutes of Health. c1993-2010 [reviewed 2009 Dec; published 2010 Jan 3]. Mitochondrial DNA. Available from: http://ghr.nlm.nih.gov/chromosome=MT.

Russell PJ, Wolfe SL, Hertz PE, Starr C, McMillan B. Biology: The dynamic science. Thomson Higher Education; Belmont, CA: 2008.

Sadava D, Heller HC, Orians GH, Purves WK, Hillis DM. Life: The science of biology. 8th Ed. W.H. Freeman & Co.; Gordonsville, VA: 2008.

21. Ubiquination is the process of marking a protein with ubiquitin so that it can be degraded by proteasomes at the end of its lifespan. This is important because each protein has a certain lifespan, and needs to be recycled after completion of that lifespan. This process is not completely understood. It may be important in treating diseases because drugs can be given to inhibit proteasomal digestion.
The following steps occur during ubiquination:
a. Ubiquitin ligases (enzymes) transfer ubiquitin to target proteins. These enzymes determine life or death. This is an important area of research. The protein is marked with the ubiquitin via covalent bond.
b. Proteasomes recognize the protein, remove the ubiquitin chain, and unfold the protein.
c. The protein becomes a linear polypeptide, and travels through the central chamber of the proteasome.
d. The protein is digested into small peptides, then released into the cytosol, where it is degraded into amino acids.
This process is so important because cells can control how long parts live. It is understood how it happens, but it is not understood why. Further understanding will likely yield new treatments.

22. Heat Shock Proteins
23. Chaperones
Chaperones are proteins that assist in the non-covalent folding/unfolding and assembly/disassembly of other macromolecules.
There are several types of chaperones:

  • steric chaperones: convey steric information (ie: how much space should be occupied by the finished product) and directly assist in the folding of specific proteins.
  • chaperones as anti-aggregates: prevent newly synthesized polypeptide chains and assembled subunits from aggregating into non-functional structures.
  • chaperones as heat-shock proteins: chaperones are sometimes referred to as heat-shock proteins because of the tendency for aggregation to occur as proteins are denatured by stress. However, not all chaperones are heat-shock proteins.
  • chaperones which help fold newly made proteins as they are extruded from the ribosome. Most newly synthesized proteins can fold in the absence of chaperones, but a minority require them.
  • chaperones involved in the transport across membranes (mitochondria and endoplasmic reticulum), protein degradation, cell death and in responding to diseases linked with protein aggregation (eg: prions).

Note that a crowded cytosol environment will accelerate the folding process (in order to make more room) and can lead to mis-folded proteins. It is speculated that crowding can increase the effectiveness of the chaperones (eg: GroEL) which counteract this folding inefficiency.
One of the most common examples and the first identified chaperone assists in the assembly of nucleosomes from folded histones and DNA.

24. Electron Transport Chain

The Electron Transport Chain (ETC) occurs in the Mitochondria and is a process in aerobic respiration. Anywhere from 32 to 34 ATP’s are produced through the ETC (and all but 2 ATP’s are created during “aerobic” respiration). ATP is broken down to create energy for things such as muscle contractions and active transport across membranes. The ETC occurs after the citric acid cycle. NADH and FADH2 (produced via glycolysis and the citric acid cycle) are electron carriers in the mitochondrial matrix that still hold energy after glycolysis and the citric acid cycle. Electrons from NADH are given to coenzyme Q by NADH dehydrogenase; and during this process, protons are moved “outside”, into the intermembrane space. Those electrons are carried to cytochrome bc1 complex by coenzyme Q (where more protons are put out into the intermembrane space. Coenzyme Q also picks up electrons around this stage from FADH2; and during this, protons are again moved into the intermembrane space. From cytochrome bc1, the electrons are carried to the cytochrome C oxidase complex by cytochrome C. Once again, at this stage, protons are moved “outside” into the intermembrane space. The electrons are then given from cytochrome C oxidase complex to oxygen (final acceptor) that combines with two hydrogen ions to form a water molecule. If there isn’t an oxygen to accept the electrons, electrons can’t continue to pass through the chain, and aerobic respiration would not continue. Protons that were in the intermembrane space “re-enter” through the ATP synthase, special proton channel proteins. This movement creates energy which is used to perform oxidative phosphorylation (creation of ATP from ADP and phosphate).

25. Co-Enzyme Q 10

*A component of the electron transport chain during aerobic cellular respiration that generates energy in the form of ATP (mechanism mentioned above)
*Serves as an electron carrier. This co-enzyme readily accepts and gives away electrons.
*Because of its ability to accept loose electrons, it is an antioxidant, and has been used as an oral supplement.
*Has been studied as a treatment for many diseases, however most studies have been inconclusive.

Reference: Langsjoen P. Introduction to Coenzyme Q10. 1994. Available from: http://faculty.washington.edu/ely/coenzq10.html

Interesting findings: Recently studied as an exercise supplement, and found to increase mean power during repeated bouts of supramaximal exercise in sedentary men in a randomized, double-blind, crossover study.

Reference: Gokbel H. The effects of coenzyme Q10 supplementation on performance during repeated bouts of supramaximal exercise in sedentary men. Jstrength Cond Res. 1 Jan 2010;24(1): 97-102.

26. G -coupled Proteins

These proteins are important signal transducing molecules in cells.

Made up of three subunits: alpha, beta, gamma….. the alpha unit is considered the active unit as it binds GTP (guanine triphosphate) when activated

Set of structures that convert external signals to intracellular responses through a second messenger system: g-coupled protein receptors, ion channels, neurotransmitters, g-coupled proteins.

Process:

A neurotransmitter binds to the g-coupled protein receptor which in turn activates a g-coupled protein. This protein then binds GTP instead of GDP and binds to a protein ion channel opening it and causing ion flow.

The g-coupled protein can also bind to another protein instead of the ion channel to initiate intracellular responses. An example of this is its binding to adenylyl cyclase which is responsible for turning ATP into cAMP which then activates protein kinase which can cause ion channels to open.

So what? initiate EPSP or IPSP, respond to different things throughout the body such as hormones, neural signals, light, smell….. help maintain homeostasis and function throughout the body…… Are the target of many pharmaceutical agents

27. 2nd messengers
Second messengers are molecules that relay signals recieved at receptors on cell surfeces- such as arrival of protein hormones, growth factors- to target molecules in cytosol and or nucleus. They are part of a secondary messenger system, which is a method of cellular signaling whereby a diffusible signaling molecule is rapidly produced and sent to activate effector proteins within the cell to exert a cellular response.

Ex. Epinephrine cannot pass through the cell membrane so a secondary messenger is used to activate the cellular response. Epinephrine binds to receptor which is linked to G-proteins which relays message to adenylate cyclase and removes two phosphate groups from ATP to convert to cAMP.

Cyclic AMP (cAMP), a second messenger, activates enzymes called kinases in the cytosol to trigger physiological changes in the cell.

G-proteins and the second messenger system play such an enormous range of roles in physiology and disease that Martin Rodbell and Alfred Gilman revieved a 1994 Nobel Prize for discovering them.

Up to 60% of currently used drugs function by altering the activity of G-proteins and cAMP.

28. Lipid Rafts

  • Micro-domains of the cell membrane rich in cholesterol and sphingolipids (fatty acids mostly found in brain and nervous tissue)
  • Also rich in signaling molecules (transmembrane and intracellular) and proteins, which are closely packed due to a special arrangement of lipids
  • Lipid rafts are crucial for signal transduction, cellular adhesion, axon guidance, vesicular trafficking, and synaptic transmission, providing neurons with a mechanism to regulate these events
  • Because of high concentration of cholesterol in lipid rafts, people with high cholesterol will experience increased stiffness of their cell membranes.

29. Cytochrome C

Important Feature of Structure:

  • Cytochrome C is an electron-transfer heme protein within the inner lining of the mitochondria and carries 1 electron
  • Single polypeptide chain of 104 amino acids
  • Easily separated from mitochondria secondary to its solubility in water

Importance of Function

  • Important in oxidation (loss of an electron) and reduction (gain of an electron) in the cell
  • An intermediate in apoptosis (controlled cell death)
  • Vital link in electron transport chain necessary to create chemiosmotic gradient for ATP synthesis
  • Contributes to the equilibrium between membrane and free forms

So What?

  • Used in many studies for molecular (and species) evolution, electron transport, and molecular immunology
  • Presence of cytochrome c increases 2 fold in leg muscles in rats after prolonged exercise
  • Has adaptive changes in its concentration as a response to exercise and is dependent on intensity
  • Increases in its mitochondrial content allows for increased capacity to perform endurance exercise

Reference:
Booth FW, Holloszy JO. Cytochrome c turnover in rat skeletal muscles. Journal of Biological Chemistry. 1977;252:416-419.

30. Trophic Factors

  • Trophic factors are small proteins that have receptors on the surfaces of nerve cells that allow a neuron to develop and maintain connections with nearby neurons. They are essential for the nerve cell to survive. Researchers have found that trophic factors can save dying neurons in animal models of ALS, but have been unsuccessful in human models as they can't reach the target cells.

31. Growth Factors

  • Growth factors are a protein or steroid hormone that stimulates cellular growth, proliferation and differentiation. They typically act as signaling molecules between cells and often promote cell differentiation and maturation, but can vary between different types of growth factors. For example, there is insulin growth factor (IGF) which can promote cell proliferation, inhibition of cell death and is required for early development. Growth factor differs from trophic factors by having the ability to stimulate cell growth and proliferation.

32. Cytokines
• Cytokines are small protein released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells, which mediate and regulate immunity, inflammation, and hematopoiesis. The cytokines includes the interleukins, lymphokines and cell signal molecules, such as tumor necrosis factor and the interferons, which trigger inflammation and respond to infections. They are produced by lymphocytes . Ctyokines act thru an autocrine regulators (produced and act on the same tissue of an organ) or paracrine regulators (produced and within one tissue and act on another within the same organ)
Fox, S I. Human Physiology 8th edition. McGraw-Hill, 2004.
33. Matrix Metalloproteinases
Matrix metalloproteinases

Matrix metalloproteinases (MMPs) are enzymes that degrade ECM. They are key regulatory molecules in the formation, remodeling and degradation of all extracellular matrix (ECM) components in both physiological and pathological processes in various tissues. These proteinases play a central role in many biological processes, such as embryogenesis and organ formation, normal tissue remodeling, wound healing, and angiogenesis. They are regulated by tissue inhibitor of metalloproteinases TIMP. Cytokines, growth factors, and hormones have been found to regulate expression of MMPs and their inhibitors, TIMPs, in a complex manner.

So what factor:
If the TIMPS inhibitors are not doing their job, (aka. Loss of activity control) there can be an imbalance of MMP activation which could result in too much ECM degradation. This could in turn result in diseases such as arthritis, cancer, atherosclerosis, aneurysms, nephritis, tissue ulcers, and fibrosis. Therefore, the control of MMP is an important therapeutic targets for the treatment of various diseases where tissue degradation is part of the pathology, such as cancer and arthritis.

Favorite thing:
There are 23 different types and Two particular MMPs are thought to be associated with the pathology of DMD. The degeneration and regeneration process is compromised and gradually becomes in favor of degeneration. Therefore, it is promising that if you can determine which MMPs are involved and control the MMP concentration, you might be able to help with diseases that involve a degeneration process

34. p 53
P53 is a tumor suppression gene important in the cell cycle and cell apoptosis. It is located on chromosome 17
and considered the “guardian of the genome”. The level of p53 must be regulated and if defective it can result in cancer secondary to allowing abnormal cells to proliferate.

35. Fluid Mosaic Model
36. Telomeres

Telomeres are sequences at the end of chromosomes that do not contain codes for proteins so they are not genes. They protect the ends of chromosomes from damage (like the plastic ends of shoe strings protect the string from fraying), and prevent the chromosomes from fusing together into rings or to other DNA in the cell nucleus.

During cell division the chromosomes are copied by enzyme molecules. a mirror image of the 2 original strands is produced however the tips of the chromosomes are unable to be completed reproduced resulting in a slightly shorter chromosome lacking a small amount of original telomere sequence. The telomeres prevent the loss of the necessary information in the end of the chromosomes. This doesnt really affect cellular functioning until enough cell divisions have occurred and the telomeres on at least one of the chromosomes becomes critically short. These cells become unresponsive to stimulating triggers and although they can live on in the body for years they can no longer replicate themselves.

So if there is an increasing percentage of cells that reach this point termed Hayflick limit than many scienctists believe there is a connection with aging in mammals. They say that if these cells are unable to reproduce than maintenance and repair of the body becomes and increasingly difficult task.

Telomerase (part protein part RNA) which is found in mammals is capable of slowing telomere erosion, halting it altogether or lengthening telomeres. The genes that produce telomerase is found in possibly all replicating cells however these genes are inactive in most of our cells for most of our lives and active across the body only in early fetal development. Otherwise it can only be found in a few special tissues such as antibody producing immune cells, cells that replenish gut-lining, and sperm producing cells.

So What:
The majority of tumors and cancers arise is the presence of the enzyme telomerase. Without telomerase, the cells in a tumor would quickly divide so many times that their telomeres would become critically short, cell division would come stop as all the cells reached their Hayflick limits, and the small growth would likely go unnoticed. Increasing resistance to cancer necessarily comes at the cost of accelerating our decline with age. If we were to somehow increase the amount of telomerase in normal cells to slow the aging process it would necessarily expose us to increased risk for tumors and cancer.

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