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 the 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 its 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.

Single cells are the smallest form of living organisms, and the majority of species on earth successfully exist as single-cellular organisms. Invisible to our eyes without the aid of technology, they are out of detectable range until they cause a disease or are useful to us (think yeast and bacteria in San Francisco sourdough). Single cell organisms are not necessarily simpler than their “more evolved” multicellular counterparts. In fact, the majority of single-cell species in existence today do just fine. They are not simpler, less developed, or behind the times. Rather than viewing them as less sophisticated, consider their way of living as completely distinct from that of multicellular organisms. In reality, these organisms tolerate the harshest conditions, and often produce offspring rapidly without the complications of costly sex, which is actually quite progressive! Existing at the level of a single cell does not make an organism inferior to a multicellular being, just very different.

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 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 and communicate with one another, thereby creating a new entity of life, an organism. The emergence of multicellular organization and the 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 the development of the nervous system. Yet, differentiation carries some disadvantages too. Multicellular organisms cannot simply divide in half, each and every time they have to start embryonic development from a single cell called a zygote.

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

1.1 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 known as organelles, which act as “tiny organs” that allocate physiological constituents to designated areas within the cell. Organelles are membranebound compartments optimized for function so that 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 mitochondriaand hereditary information is stored in the nucleus. Of greater importance, however, is the realization that optimization of the functions comes from the beneficial grouping within the organelle of 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. 

A. Cell membrane – the cell boundary

As mentioned before, life can only exist within the confines of the plasma membrane, which is an isolating layer of lipids encasing both prokaryotic and eukaryotic cells. Membranes are made by the cell; yet cells cannot exist without the membrane. This creates the big question:  What was first, the chicken or the egg?

The cell membrane is a 7-10 nm thick layer of lipids with attached proteins and carbohydrates that fluctuate on the surface of watery droplets called cytoplasm. The main lipids that form cell membranes are phosphoglycerides, which are popularly, but incorrectly called phospholipids. Phospholipids have a polar structure that makes them assemble into a sandwich-like structure called a bilayer with hydrophobic fatty acid tails pointing in one direction and hydrophobic alcohol groups in the other.

In addition to phospholipids, other lipids with different properties participate in the formation of the membrane — they are glycolipids (mostly sphingolipids) and a class of sterols, with the most common of them being cholesterol.

The proteins embedded in the cell membrane perform cellular functions, such as transportation of nutrients and waste into and out of the cell, reception of signals from the outside of the cell or expression of cell identity, and cell contact with other cells or extracellular matrix. 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 an ever-changing number of glucose transporters for the transport of glucose into and out of storage in the liver. Expression of membrane proteins differs with cell function and adjusts accordingly to the metabolic activity of the cell. Carbohydrates that are attached only to the outside leaflet of the bilayer regulate adhesion of the cell and serve as cell surface markers for immune responses. A lipid bilayer is a great insulator and supports the structure, keeping the content all wrapped up.

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

Prokaryotic cells are smaller than eukaryotic cells and all metabolic functions are performed in one undivided space. 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 internal membrane system partitions the interior of a eukaryotic cell into membrane-bound compartments called organelles. The presence of organelles, one of them being the membrane-bound nucleus, is probably the most defining difference between these two types of cells. 

Eukaryotic human liver cell, prokaryotic Salmonella typhimurium, and virus HIV virus showing the size difference between the tiny virus, small prokaryotic cell, and larger eukaryotic cell.
Figure 1: eukaryotic vs. prokaryotic cell

C. 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 the endoplasmic reticulum.

Endoplasmic reticulum – walls within the cell

Endoplasmic reticulum (ER) consists of a large number of membrane vesicles that divide inside of the cell into two major spaces, a cytosol and “out of cytosol”. The “out of cytosol” space is the lumen of the ER. The major role of ER is to create a space within the cell that is isolated from the cytosol, both for sequestering molecules that can damage the cell (you probably remember that ER is a place of calcium storage and inactivation of toxins) and creating conditions where new molecules, especially proteins, can be properly assembled and modified before being delivered to their final location within the cell, or secreted to the outside. As the biggest network of internal membranes, ER is also the anchoring site for enzymes involved in fatty acid and phospholipid synthesis.

Parts of the ER where the synthesis of proteins 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.

Notice that proteins are produced by ribosomes attached to the external surface of the ER membrane and “injected” into ER and NOT, as it is often mistakenly stated, by the rough ER.

Golgi complex – a delivery system of the cell

The Golgi complex is a structure made of hundreds of flattened vesicles that process, package, and distribute molecules coming from the ER. The Golgi has a distinct structure of parallel cup-shaped sheets. It is divided into three regions—cis, medial, and trans—each with its own set of molecular markers. The Cis region is the entry point and is created from merging ER vesicles with vesicles that carry the specific “cis” enzymes. The Trans-Golgi region, the last in Golgi maturation process, distributes the proteins and lipids to their final destinations within the cell. Proteins enter the Golgi apparatus on the convex, or forming face, side and exit on the concave, or maturing face, side.

Vesicular traffic – ER to Golgi and beyond

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 proteins 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 throughout their journey and are given names based on the presence of biochemical markers. Vesicles that just formed from the cell membrane and bring inward substances that came into the cell by endocytosis are called endosomesAs endosomes merge and acquire new properties, they change their molecular signature and the name to sorting, recycling, and finally 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 the endosomal-lysosomal pathway is the digestion of materials brought into the cell by endocytosis (or phagocytosis) such as nutrients or removal of molecules that are no longer neededEndosomes can also “swallow” old and no longer needed organelles in a process called autophagyDuring prolonged starvation cells use autophagy to obtain energy and assure survival through conserving critical cellular functions. Figure 2 shows an illustration of this process. 

Figure 2: Endomembrane system in the eukaryotic cell.

Lysosomes – recycling centers of the cell

Lysosomes are acidic vesicles responsible for digesting molecules that are brought from the cell’s exterior through endocytosis, phagocytosis, or autophagy.  Lysosomes maintain a very low pH inside due to the 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 digestive enzymes. As mentioned above, lysosomes are one of many vesicles located near the plasma membrane that constantly merge with others and perform the enzymatic breakdown.

Malfunction of lysosomal enzymes usually has very severe consequences for the cell. The undigested substance accumulates in the cell leading to the deterioration of other cell components. Lysosomal storage diseases, usually genetic mutations in the genes for 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, and probably the most well understood, of the lysosomal storage diseases because of its severity.  It is fatal at an early age and still remains untreatable, although the etiology of the disease is known. Tay-Sachs disease causes a buildup of undigested gangliosides, causing extensive and irreversible damage to the neurons in the central nervous system.

Follow this link to read more about lysosomal storage diseases.

Link to lysosomal storage disease

D. Peroxisomes

Peroxisomes are organelles that are responsible for the oxidation of fatty acids. In contrast to oxidation in mitochondria, oxidation is not coupled to ATP production, but dissipated as heat.  

E. Nucleus – a control center of the cell

The nucleus is the largest, centrally located organelle, and the one clearly visible with a light microscope.  Robert Brown first described it in 1831, and for a few years until the electron microscopy age, it was the only organelle possible to be seen. The nucleus, that houses DNA, is enveloped by a 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 the ER lumen. The nuclear envelope is supported on the inside by a network of intermediate filaments called lamins. Mutations to the lamin A gene destabilizes the nuclear envelope and results in progeria, a disease that causes accelerated aging. The nuclear membrane disassembles before cell division, liberating DNA into the cytoplasm to complete chromosome division. It reassembles into a new nucleus upon completion of cell division.

There is a significant amount of traffic flowing between the nucleus and cytosol. The nuclear membrane contains nuclear pores which are places of selective transport between cytosol and the 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 the nuclear envelope are pinched together by a ring of eight nucleoporin subunits arranged around the central plug. The central plug is a transporter. Nuclear pores are 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 the surrounding nucleoplasm and visible in electron microscopy as nucleoli, dark spots that move from place to place depending on what part of the genome is being actively transcribed. The nucleolus is not an organelle; it just is a region of increased concentration of RNA and proteins.

F. 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 them into four distinct spaces, each with its own set of proteins and functions. The mitochondrial matrix contains enzymes of the 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 the Electron Transport Chain (ETC). The 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. Mitochondrial ribosomes resemble prokaryotic ribosomes.

The inner mitochondrial membrane separates the matrix and intermembrane space and contains redox driven pumps of the Electron Transport Chain. ETC is a chain of 4 multiprotein complexes that pump protons into the intermembrane space while powered by the energy of “falling” electrons and creating a proton gradient. The 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 the intermembrane space back to matrix is used to add inorganic phosphate to ADP and produce ATP. More details about oxidative phosphorylation are in Chapter 3.

The mitochondrial outer membrane has a high protein to 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 also play a role in aging.

G. Cytosol

Filling the rest of the cell is the cytoplasm. The cytoplasm contains all of the organelles, as well as the cytoskeletal fibers, ribosomes, and metabolic enzymes.  The cell has to be held together by some kind of framework, called the cytoskeleton, a network of protein filaments that support the cell and affect the cell’s movement. Acting as tracts for the movement of structures within the cell, it is dynamic, constantly assembling and disassembling. There are three different kinds of fibers that make up the cytoskeleton:

  • microfilaments
  • intermediate filaments
  • microtubules

Each fiber has its own type of protein, but all are protein polymers.

Cytoskeleton are fibers, not organelles. They not only reinforce cells but also, in multicellular organisms, support the integrity of multicellular blobs called tissues, or adhesions to other cells and matrix through specialized cell junctions, or adhesions.

 

 

 

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Histology Copyright © by Malgosia Wilk-Blaszczak. All Rights Reserved.

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