1 The Cell: a basic unit of life

In the current conditions on Earth, both on land and in water, life can only exist within the confines of a membrane-bound vesicle called a CELL. Cells come in different shapes and sizes. Cells can exist as single-cell organisms or as units within multicellular creatures. Each cell is a self-sustainable, self-reliant unit that can replicate itself and carry on all the metabolic processes essential for the continuation of life.  Each cell of both single and multicellular organisms holds the keys necessary to produce viable offspring.  All cells carry genetic material called DNA for transfer of hereditary information, as well as arrays of biomolecules necessary for essential life processes such as protein synthesis, cellular respiration or intracellular signaling.  All cells need a membrane to define a perimeter and separate its living components from the outside.  Without a genome, a cell has no information, and without an intact membrane, a cell has no organization.

In multicellular organisms, the cells are not identical, but they are grouped into tissues, the cell assemblies that through differential expression of the genome became specialized for a particular function. So although every cell carries a full genome and potential information for a self-sustained living, cells of multicellular organisms rely on each other and cooperate in optimizing the functioning of the entire organism. Multicellular organisms are more than colonies of single cells; they are assemblies of cells that depend on each other, communicate with one another, thereby creating a new entity of life, an organism. The emergence of multicellular organization and differentiation of cells into tissues and organs gave multicellular organisms the opportunity to develop sophisticated functions not possible in unicellular creatures such as independent movement or development of the nervous system. Yet, differentiation carries some disadvantages too. The multicellular organisms cannot simply divide in half, each and every time they have to start the embryonic development from a single cell called a zygote.

No domain of life, unicellular or multicellular, is superior over another. Each divergent branch evolved with purpose and follows different paradigms along the pathway to their successful existence today.

Eukaryotic organisms; the emergence of organelles

In general, the classification of cells is associated with the presence or absence of a nucleus, the biggest and at one time until the dawn of the electron microscopy age, the only visible organelle found exclusively in eukaryotic cells.  Although the nucleus or “karyon” is the major identifiable characteristic of eukaryotic cells, simple possession of this organelle is not the standalone attribute setting it apart from prokaryotic cells.  Rather, it is the presence of the internal partitioned spaces acting as “tiny organs” that allocates physiological constituents to designated areas within the cell. Organelles are membrane-bound compartments optimized for a function so a cellular business can be more efficiently conducted.  Each of us can easily recite the organelles and their respective duties: cellular digestion occurs in lysosomes, energy production comes from mitochondria and hereditary information is stored in the nucleus.  Of greater importance, however, is realization that optimization of the functions comes from the beneficial grouping within the organelle of the molecules that are involved in sequential steps of reactions or perform similar functions. In essence, by incorporating the “fencing” system afforded by biological membranes at the sub-cellular level, organelles naturally introduce a way of sequestering unique function to an enclosed space, creating inside each organelle the conditions ideal for that specific function.

By using this design eukaryotes effectively diversified as organisms and streamlined biochemical pathways to the benefit of individual cells.  Additionally, with the emergence of multicellular organization/life and differentiation of cells into tissues and organs, the existence of organelles appears to work favorably in support of communities of eukaryotic cells having highly specialized functions. Cells that are a part of an operational entity are still independently sustainable units but sacrifice a bit of freedom and individuality of the single life for the benefit of an unified network with a common cause.  The concept of envelopment alone does not give organelles their “biochemical signatures” or confer function.  In fact, all membrane-bound vesicles eventually merge at some point by fusing to each other or the cell membrane; changes to these otherwise homogenous transitory elements come only through acquiring protein markers specific to each organelle.

It is the presence of these specific proteins that truly imparts specialized function to each cellular landmark.  Throughout various physiological processes, progressive alterations to the proteome continually drive stages of cellular cycles and move processes to maturation.  Organelles themselves are indistinguishable without determinate proteins to guide and regulate their intended tasks.  The importance of these powerful cellular directors will be a common theme reintroduced throughout the book.  This chapter summarizes the functions of the organelles with the emphasis on how the cells direct the proteins to the appropriate compartments and keep them there; and how the separate functions of the organelles relate to overall unified cell function.

Cell membrane – the cell boundary

As mentioned before life can only exist within the confines of plasma membrane, which is

an isolating layer of lipids encasing both prokaryotic and eukaryotic cells. But life is not self sustained within cell boundary and cell membrane cannot be seen as a solid partition separating two non-interacting environments. Food has to be brought in, waste removed and intracellular metabolism adjusted to assure that it corresponds to conditions outside. The proteins embedded in cell membrane ensure cellular functions are performed at the level consistent with continuation of life despite dynamically changing needs of the cell. While the proteins vary from cell to cell, the membrane itself is a highly homologous structure having a uniform chemical composition that attributes greatly to its success as a cellular barrier.

Both prokaryotic and eukaryotic cell membranes constantly undergo remodeling to accommodate cell surface activity. Also called the plasma membranes, they are double layer of lipids with the proteins embedded in it that make it an ideal permeable protector for the cell.  A lipid bilayer is a great isolator, and supports the structure keeping the content all wrapped up. It is built from lipids and steroid derivatives. The main phosholipids are phosphoglycerides that are popularly but incorrectly called phospholipids. In addition to phospholipids other lipids, with different properties participate in formation of the membrane – they are glycolipids (mostly sphingolipids) and a class of sterols with the most common of them being cholesterol. Phospholipids have a polar structure that makes them assemble into flat polarized sheets with hydrophobic fatty acid tails pointing in one direction and hydrophobic alcohol groups in the other. In addition, in watery environment o life two sheets of phosphlipids (called leaflets) assemble in a sandwich-like structure called a bilayer. Most cells have true bilayers made of two separate leaflets, with Archea being the exception.  These organisms have a slightly different cell membrane structure that is a monolayer but for practical purposes it looks and behaves like a bilayer with hydrophilic part facing outside. More details on aspects of biomembrane structure and function will be discussed later in this course.

Expression of membrane proteins differs with cell function and adjusts accordingly to metabolic activity of the cell.   This class of proteins is responsible for the more “subtle” aspects of cell function – transport, reception of signals, expression of cell identity or in multi-cellular organisms contact and communication with other cells. They give the membrane its identity, for example kidney epithelial cells express a large number of aquaporins (water channels) and transporters for increased reabsorption of water, sugar and ions. Neuronal membranes have voltage-gated ion channels that control membrane potential and make the membrane excitable and liver cells have ever-changing number of glucose transporter for transport of glucose into and out of the storage in liver.  In short, the proteins embedded in the bilayer give the membrane its specific function. We will study the functions of membrane proteins for better part of this course.

Size matters – necessity for subdivisions in eukaryotic cells vs. simple fit in one prokaryotic container.

prokaryotic versus eukaryotic cell
Prokaryotic and eukaryotic cells vary in size and complexity

Prokaryotic cells are smaller than eukaryotic cells and all metabolic functions are performed in one undivided space. Due to this sizably smaller scale, the availability of substrates and probability of interactions between molecules doesn’t create major problems; chances of an enzyme making contact with substrate are highly likely.  With the increase in cell size and wealth of metabolic functions came the need for sequestration and optimization of those processes into separate spaces. The “growing” eukaryotic cell that is on average two orders of magnitude larger than a prokaryotic cell needed internal compartments that would divide

the cell into separate spaces and increase concentrations of metabolites and enzymes so reactions can be performed more efficiently. The evolving

internal membrane system partitions the interior of eukaryotic cell into delimited spaces rather than keeping one big metabolically identical “blob.”

These membrane-bound compartments called organelles, contain specialized assortments of proteins (including but not limited to enzymes) that makes each organelle a space optimized for function.  Examples of this are enzymes for energy productio

n are all localized in mitochondrion while hydrolytic enzymes are found in highest concentration in lysosomes, which are sites of waste destruction.  The presence of organelles, one of them being the membrane bound nucleus, is probably the most defining difference between these two types of cells.

Emergence and evolution of internal membranes in eukaryotes.

Compartmentalization of the cells with internal membranes provided separation of functions into distinct organelles. Each organelle is a closed vesicle with unique molecular identity, a set of proteins that impart its functions. The biggest network of internal vesicles is endoplasmic reticulum.

Endoplasmic reticulum – walls within the cell

Endoplasmic reticulum (or ER) consists of a large number of vesicles that divide the cell into two major spaces, a cytosol and “out of cytosol,” meaning the inside the lumen of the ER. The major role of ER is to create a space within cell limits that is isolated from the conditions of the cytosol, both for sequestering molecules that can damage the cell (you probably remember that ER is a place of calcium storage) and creating conditions where molecules ultimately destined to the outside of cell (such as extracellular matrix protein collage, or hormones) can be properly modified and prepared for assuming their function without exposure to the deleterious, detrimental effects of the cytoplasmic environment.

ER lumen is a place of calcium storage, impounding and sometimes inactivation of toxins. As the biggest network of internal membranes, ER is also the anchoring site for enzymes involved in fatty acid and phospholipid synthesis. ER is also intermediate stop for proteins that are intrinsic membrane proteins or are later secreted outside of the cell such as hormones and extracellular matrix proteins.  These proteins are translated by ribososmes directly resting on the surface of the ER and immediately “injected” into a lumen for further processing or are threaded through the ER membrane.  ER lumen contains many modifying enzymes, chaperones, lectins and other molecules that take part in posttranslational modifications of newly translated proteins. ER lumen is a place where the newly synthesized proteins that are not destined for cytosol, nucleus or mitochondria as their final location can “hide” while folding, assembling into final multi-subunit complexes or being modified.

Parts of the ER where the synthesis and “injection” takes place are studded with ribosomes and appear “rough” on electron micrographs in contrast to parts of ER that are quiescent and appear “smooth.”  Ribosomes disassemble after translation and the same parts of the ER are rough or smooth at different times during the cell’s life. In cells that produce a lot of secreted proteins, such as hormone producing endocrine organ cells, the majority of ER will be rough.

Please notice that proteins are produced by ribosomes attached to the external surface of ER membrane and injected into ER through a translocon and NOT, as it is often mistakenly stated, inside the rough ER.

Golgi complex – a delivery system of the cell.

After synthesis and posttranslational modifications in the ER proteins have to be sorted and delivered into their destination organelles or cell surface. Sorting and packaging proteins for delivery is a function of Golgi complex also known as Golgi apparatus.

Golgi complex is a structure made of hundreds of flattened vesicles that process, package and distribute molecules coming from the ER. Similarly to the ER, Golgi contains modifying enzymes, including those that will continue posttranslational modifications of proteins and lipids.

Golgi has 3 regions, cis, medial and trans, each with its own set of molecular markers. Golgi cisternae undergo maturation that is the result of acquisition of new enzymes and changing functions. Cis region is the entry point and is created from merging ER vesicles with vesicles that carry specific “cis” enzymes. With each step of maturation, enzymes are recycled to the previous step while proteins move on. Final sorting at trans-Golgi level distributes the proteins and lipids to their final destinations, mature and ready to assume their function.

Vesicular traffic

Vesicles in the cell are responsible for moving proteins and phospholipids around. They are constantly in motion, merging and detaching, traveling between organelles and cell surface transporting both newly made protein to the cell surface in the process of exocytosis and bringing proteins into the cell for digestion in lysosomes in the process of endocytosis. All these vesicles change through their journey and are given names based on the presence of biochemical markers, proteins located both inside and on their surface but in fact they are still made from same membranes they started from.  Vesicles that just formed from the cell membrane and bring inward substances that came into the cell by endocytosis are called endosomes.

Some substances move into and out the cell in membrane vesicles.

Similarly to Golgi, as they merge and acquire new proteins they change their molecular signature and the name to sorting, or recycling or late endosomes. The names are sometimes confusing, as the similar vesicle that is formed by phagocytosis will be called a phagosome. Both endosomes and phagosomes can merge with a lysosome (that delivers enzymes for digestion characteristic of lysosome) and become a secondary (active) lysosome. The function of endosomal-lysosomal pathway is digestion of materials brought into the cell by endocytosis (or phagocytosis) such as nutrients (the LDL particle that needs to be degraded to get the cholesterol and free fatty acids out of it), degradation of membrane proteins to recover amino acids, or removal of no longer needed ligands bound to cell surface receptors to terminate a signaling event. Endosomes can also envelop old and no longer needed organelles in a process called autophagy. During prolonged starvation cells use macroautophagy, a process of digesting its own cytoplasm, to obtain energy and assure survival through conserving critical cellular functions.

 

Lysosomes – recycling centers of the cell

Lysosomes are acidic vesicles responsible for digesting molecules that are brought from the cell’s exterior either through endocytosis, phagocytosis or by engulfing into a vesicle no longer needed internal cellular components.  Lysosomes maintain very low pH due to the ATP-driven V-type proton pumps in their membranes. In the absence of ATP, the protons leak out into the cytoplasm and lyse the cell due to the sudden rise in acidity.

Lysosomes contain several dozens of acid hydrolases including proteases, lipases or amylases.  As mentioned above lysosomes are one of many vesicles located near the plasma membrane that constantly merge with others and deliver proton pumps and enzymes to late endosomes to start enzymatic breakdown. Usually the name of lysosome is reserved for the final, most acidic stage of degradation in vesicles.

Malfunction of lysosomal enzymes usually has very severe consequences for the cell. The undigested substance accumulates in the cell leading to deterioration of other cell components. Lysosomal storage diseases, usually genetic mutations to one of the enzymes, manifest themselves at an early age, progress quickly and are usually fatal.

Tay-Sachs disease, which is caused by β-Hexosaminidase A deficiency was the first described, probably the most well understood of the lysosomal storage diseases because of its severity.  It is fatal at early age and remains untreatable still although the ethiology of the disease is known.  Tay-Sachs disease causes a buildup of undigested gangliosides, causing extensive and irreversible damage to the central nervous system.

Other lysosomal storage diseases have less severe progression and are for example:

Pompe’s disease – The inability to breakdown excess glycogen causes it to accumulate in skeletal and cardiac muscle cells causing weakness and eventual failure of the entire muscles.  Pompe’s disease is a deficiency of acid α glucosidase.  Recently approved recombinant enzyme replacement therapy using IV infusions prolongs life of the patients but the treatment has many serious side effects and has to be administered indefinitely.

The most common storage disease, Gaucher disease, is caused by mutations in the lysosomal enzyme glucocerebrosidase, which in normal individuals is responsible for breakdown of glycoproteins from a worn out cell membranes. Inadequate production manifests itself by accumulation of glucocerebrosides within phagocytes throughout the body.

Alkaptonuria is a lack of homogentisic oxidase, which when the body lacks blocks phenylalanine-tyrosine metabolism. With this disease homogeneitic acid accumulates in the body, binding to collagen in connective tissues, tendons and cartilage and staining it blue-black. Clinical signs of this disease are blue-black pigmentation (onchronosis) in the cartilage of ears, nose and cheeks, as well as osteoarthritis from buildup of pigment in the joint cartilage.

Follow this link to read more about lysosomal storage diseases.

Other functions of lysosomes involve destruction of invaders (bacteria) in white blood cells or break down of signaling molecules brought in from the surface in endocytic vesicles to stop the signaling.

Peroxisomes

Peroxisomes, the single membrane organelles are responsible for oxidation of fatty acids.In contrat to oxidation in mitochondria, oxidation is not coupled to ATP production, but dissipated as heat.  This organelle also protects the cell from hydrogen peroxide, a byproduct of oxidations in the cells, it contains peroxidases and catalase.

Nucleus – a control center of the cell

Nucleus is the largest, centrally located organelle and one clearly visible with light microscope.  Robert Brown first described it in 1831, and for few years until the electron microscopy age it was the only organelle possible to be seen. Nucleus, that houses DNA, is enveloped by nuclear envelope that on the cross-section looks like two membranes separated by a narrow space (a double membrane). The space between two membranes of the nuclear envelope is a part of ER that folds as a very flattened vesicle, and is therefore continuous with ER lumen. Nuclear envelope is supported on the inside by a network of intermediate filaments called lamins. Mutations to the lamin A gene destabilizes nuclear envelope and results in progeria, a disease that causes accelerated aging. Nuclear membrane disassembles before cell division liberating DNA into a cytoplasm to complete chromosome division.  It reassembles into new nucleus upon completion of cell division.

There is significant amount of traffic flowing between nucleus and cytosol. The nuclear membrane contains nuclear pores that are place of selective transport between cytosol and nucleus. For example, proteins such as transcription factors or ribosomal proteins constantly travel from one side of the nuclear membrane to the other. Selectivity of the transport through nuclear pores is ascertained by the presence of the nuclear pore complexes.  At the nuclear pore the two membranes of nuclear envelope are pinched together by a ring of eight nucleoporin subunits arranged around the central plug. The central plug is a transporter.  Nuclear pore is not a size filter; in fact many molecules dimerize prior to entering the nucleus.

Nuclear DNA is constantly transcribed in varying regions of the genome. The regions of increased activity, especially ribosome assembly, are denser than surrounding nucleoplasm and visible in electron microscopy as nucleoli, dark spots that move from place to place dependent on what part of the genome is being actively transcribed. Nucleolus is not an organelle; it just is a region of increased concentration of RNA and proteins.

Mitochondrion: the cell’s chemical furnace

Mitochondria are the site of oxidative metabolism and ATP production. They are unique in their proposed origin as it appears that they once lived as symbiotic, aerobic bacteria that eventually became engulfed by eukaryotic cells as they came into existence. Mitochondria have two membranes that divide this organelle into four distinct spaces, each with its own set of proteins and functions. The mitochondrial matrix contains enzymes of Krebs cycle, as well as mtDNA and ribosomes. Circular mtDNA is inherited maternally.  It encodes mitochondrial 2 rRNA, 22 tRNA and 13 mitochondrial proteins of Electron Transport Chain. Majority of mitochondrial genes have been transferred into nuclear DNA, and resulting proteins are synthesized in cytosol and post-transitionally imported into the organelle. Highly homologous to prokaryotic DNA, mtDNA does not contain introns or long noncoding sequences. Ribosomes resemble prokaryotic ribosomes.

The inner mitochondrial membrane separates matrix and intermembrane space and contains redox driven pumps of Electron Transport Chain. ETS is a chain of 4 multiprotein complexes that pump protons into the intermembrane space while powered by the energy of “falling” electrons and creating proton gradient. Inner mitochondrial membrane also contains an ATP producing enzyme, ATP synthase. ATP synthase is a V-type proton pump that works in reverse. The energy of protons flowing down the gradient from intermembrane space back to matrix is used to add inorganic phosphate to ADP and produce ATP.

Mitochondrial outer membrane has high protein: lipid ratio in the cell. The large number of proteins includes transport proteins for pyruvate, ATP/ADP, and reduced nucleotides.

In addition to ATP production mitochondria are also involved in apoptosis, cholesterol and steroid hormone synthesis, and play a role in aging.

The video below takes you on the journey through the cell

 

 

 

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