Stephen R. Bolsover - Cell Biology

The great majority of proteins of the mitochondrion are encoded by nuclear genes and synthesized in the cytoplasm. But some of the information necessary for the function of mitochondria is stored within the organelle itself. Mitochondria contain many small circular DNA molecules ( Table 1.1on page 7) that are very different from the long, linear DNA molecules in the nucleus. This is strong evidence for the endosymbiotic theory of the origin of mitochondria (page 7), which proposes that the small circular DNA molecules found in mitochondria are all that is left of the chromosomes of the original symbiotic bacteria. Mitochondria also contain ribosomes (again, more like those of bacteria than the ribosomes in the cytoplasm of their own cell) which allows synthesis of a small subset of mitochondrial proteins.

Eukaryotic cells contain many sacs and tubes bounded by a single membrane. These are often rather similar in appearance and indeed if roughly spherical are lumped together as vesicles.Nevertheless, there are in fact distinct types specialized to carry out distinct functions.

Mitochondria are frequently found close to another membrane‐bound organelle, the peroxisome ( Figure 1.2on page 5). In human cells peroxisomes have a diameter of about 500 nm and their dense matrix contains a heterogeneous collection of proteins concerned with a variety of metabolic functions, some of which are only now beginning to be understood. Peroxisomes are so named because they are frequently responsible for the conversion of the highly reactive molecule hydrogen peroxide (H 2O 2), which is formed as a by‐product of the reactions in the mitochondrion, into water. This reaction is carried out by a protein called catalase, which sometimes forms an obvious crystal within the peroxisome. Catalase is an enzyme– a protein catalyst that increases the rate of a chemical reaction. In fact, it was one of the first enzymes to be discovered. In humans, peroxisomes are primarily associated with lipid metabolism. Understanding peroxisome function is important for a number of inherited human diseases such as X‐linked adrenoleukodystrophy where peroxisome malfunction and the consequent inability to metabolize lipid properly typically leads to death in childhood or early adulthood unless dietary lipid is extremely restricted.

The endoplasmic reticulum ( ER) is a network of membrane‐enclosed tubes that run throughout the cell, forming a continuous mesh whose lumen (interior) is at all points separated from the cytosol by a single membrane. The membrane of the ER is continuous with the outer nuclear membrane ( Figure 2.3). Two regions can be recognized in most cells, known as smooth ER and rough ER ( Figure 1.2on page 5). The basic difference is that the rough ER is covered in ribosomes, which gives it its rough appearance in the electron microscope.

The function of the smooth ER varies from tissue to tissue. In the ovaries, testes, and the adrenal gland it is where steroid hormones are made; in the liver it is the site of detoxication of foreign chemicals including drugs. Probably the most universal role of the smooth ER is the storage and sudden release of calcium ions. Calcium ions are pumped from the cytosol into the lumen of the smooth ER to more than 1000 times the concentration found in the cytosol. Many stimuli can cause this calcium to be released back into the cytosol, where it activates myriad cell processes ( Chapter 10).

The rough ER is where cells make the proteins that will end up as integral membrane proteins in the plasma membrane, and the proteins that the cells will export (secrete) to the extracellular medium (such as the proteins of the extracellular matrix, page 8).

The Golgi apparatus, named after its discoverer, 1906 Nobel prize winner Camillo Golgi, is a distinctive stack of flattened sacks called cisternae( Figure 1.2on page 5). The Golgi apparatus is the distribution point of the cell where proteins made within the rough ER are further processed and then directed to their final destination, the interior of the cell or the cell surface (see Chapter 12). Appropriately, given this central role, the Golgi apparatus is situated at the so‐called cell center, a point immediately adjacent to the nucleus that is also occupied by a structure called the centrosome.The centrosome helps to organize the cytoskeleton,the supporting framework of the cell ( Chapter 13).

Lysosomes vary in shape and size but are often spherical, with a diameter of 250–500 nm. They are particularly plentiful in cells that digest and destroy other cells, such as the white blood cells called macrophages. This relates to their primary function in degrading material. Indeed, lysosomes are sometimes called “cell stomachs” because they contain a battery of enzymes that digest cellular components. Over 50 such enzymes exist, responsible for the breakdown of proteins, lipids, and even damaged organelles. Many of the enzymes show an acidic pH optimum, meaning that they function most efficiently at low pH. For this reason, lysosomes maintain a pH of 4–5. This aids breakdown of the material. We shall return to lysosomes in Chapter 12.

A number of inherited diseases are characterized by cells filled with very large lysosomes. Many of these diseases involve abnormalities of development of the skeleton and connective tissues, as well as of the nervous system. The severity varies with the particular disease, but they often lead to death in infancy. In the majority of these diseases one lysosomal enzyme is missing or defective. Lysosomes work to degrade cellular components that are damaged or no longer needed and their enzymes function under the acidic conditions in the lysosome. If one of these enzymes is defective then the substrate will accumulate, filling the lysosome. The distended lysosomes eventually fill and damage the cell. Some of the best understood lysosomal storage diseases involve deficiencies in one or other of the enzymes required to degrade the complex glycosylated proteins and lipids found on cell surfaces.

Tay‐Sachs disease involves severe mental retardation and blindness, with death by the age of three. In this case an enzyme required to break down a particular complex membrane lipid called a ganglioside is missing and undegraded ganglioside accumulates, swelling the lysosomes. Gangliosides are especially important in neuronal membranes so neurons are particularly damaged.

Although organelles compartmentalize cell activity they do not work in isolation. Similarly, cells often function as a collective. Organelles and cells form both intracellular and intercellular junctions to facilitate this. We will consider both these in turn.

Organelles form junctions with other organelles and the plasma membrane via specialized structures known as membrane contact sites.Membrane contact sites are regions of close apposition whereby the membranes on either side of the junction are separated by <30 nm. They are stabilized by tethering proteins that span the junction.

The ER is a particularly well‐connected organelle. It forms membrane contact sites with most organelles, including lysosomes ( Figure 2.5), as well as with the plasma membrane. ER membrane contact sites are often tethered by a protein called VAP (VAP is short for the cumbersome name “vesicle‐associated membrane protein associated protein”!). VAPs are integral proteins of the ER that recognize and bind to specific target proteins on the apposing membrane (page 120). This is an example of a protein–protein interaction and we will meet many other examples throughout this book.