Cell Physiology

Clinical note: There are more than 45 lysosomal storage diseases, caused by impairment of lysosomal function, usually secondary to an inherited deficiency in a hydrolytic enzyme (Table 1-3). The resulting lipid accumulation within lysosomes eventually hinders the activity of cells in many organs, including the liver, heart, and brain. As with I-cell disease, clinical symptoms are severe, and average life expectancy across the entire group of diseases is approximately 15 years, reflecting the importance of normal lysosomal function.

• Mitochondria

a. These membranous organelles are composed of outer and inner membranes, intermembranous space, and inner matrix; they contain their own genetic material, mitochondrial DNA, which codes for mitochondrial proteins and transfer RNA.

Mitochondria: contain their own DNA encoding for mitochondrial proteins and transfer RNA

b. Responsible for energy production through aerobic metabolism and ketogenesis

Mitochondrial energy production: occurs through aerobic metabolism; defective in LHON (see clinical note below)

c. Mitochondria and their DNA are inherited maternally (i.e., mitochondria are received only from the egg, not from sperm).

Mitochondrial DNA: inherited maternally

Clinical note: When mitochondrial dysfunction is inherited through mitochondrial DNA, all offspring are equally affected, but only female offspring pass on the disorder. However, other types of mitochondrial dysfunction result from defects in specific proteins that are coded by nuclear DNA but function in the mitochondria, such as Leber hereditary optic neuropathy (LHON), which is characterized by loss of vision in the center of the visual field. LHON is believed to be a result of decreased mitochondrial function and resulting lack of energy in the optic nerve and retina. Disorders resulting from mutations in nuclear genes encoding mitochondrial proteins can be passed on from both male and female offspring.

3. Cytoskeleton (Table 1-4)

• This network of filaments provides mechanical support, cell flexibility, and cell motility and aids in cell division.

Cytoskeleton: provides structural support and flexibility to cell, aids in cell motility and division

• Microfilaments

a. Small-diameter, flexible, helical polymers composed of G actin and located just beneath the plasma membrane

b. Function in cell motility, organelle transport, cytokinesis, and muscle contraction

Microfilaments: myriad functions; composed of G actin

• Intermediate filaments

a. Comprise a large, heterogeneous family of proteins and are the most abundant of the cytoskeletal elements

Intermediate filaments: most abundant of cytoskeletal elements

b. Important in the stability of cells, especially epithelial cells

c. Form desmosomes, structures that attach one epithelial cell to another, and hemidesmosomes, structures that anchor the cells to the extracellular matrix

d. An example of a constituent of a membrane-bound intermediate filament is the protein ankyrin.

Intermediate filaments: form desmosomes and hemidesmosomes; example: spectrin

Clinical note: In hereditary spherocytosis, a form of hemolytic anemia, most patients have mutations in the ankyrin gene, which causes impaired function of the membrane protein spectrin in red blood cells (RBCs). The characteristically spherical, mechanically unstable, and relatively inflexible RBCs tend to rupture within blood vessels and, because of their inflexibility, become lodged and subsequently scavenged within the splenic cords, resulting in a decrease in the number of circulating RBCs. The classic presentation is jaundice, splenomegaly, and anemia that typically resolves after splenectomy.

4. Non–membrane-enclosed organelles

• Centrioles

a. Bundles of microtubules linked by other proteins

b. At least two are present in the centrosome of each cell capable of cellular division.

c. Function in cell division by forming spindle fibers that separate homologous chromosomes.

Centrioles: composed of microtubules; present in centrosome; spindle fibers separate chromosome pairs

• Cilia

a. Long, fingerlike projections of plasma membrane, differing from microvilli in that they are supported by microtubules

b. Two types: motile and nonmotile (primary) cilia

c. Motile cilia function to move fluid and/or secretions along the cell surface, whereas primary ciliary typically play a sensory role.

Cilia: motile or nonmotile; defective in Kartagener syndrome

Kartagener syndrome: ciliary dysmotility, bronchiectasis, chronic sinusitis, situs inversus

Clinical note: In Kartagener syndrome (immotile cilia syndrome), ciliary dysmotility results in the clinical triad of bronchiectasis, chronic sinusitis, and situs inversus. Respiratory tract infections occur as a result of impaired mucociliary clearance. The reason for situs inversus is unknown, although normal ciliary function is postulated to be a requirement for visceral rotation during embryogenesis. Deafness and male infertility may also result from the impaired ciliary function.

• Ribosomes

a. Consist of ribosomal RNA and protein

b. Function in protein synthesis (translation)

c. Fixed ribosomes are bound to the ER, whereas free ribosomes are scattered throughout the cytoplasm.

Ribosomes: complexes of RNA and protein, which catalyze protein synthesis using messenger and transfer RNA

E. Junctions between cells

2. Gap junctions

• Two lipid bilayers are joined by transmembrane channels (connexons) that permit passage of small molecules such as Na⁺, Ca²⁺, and K⁺; various second messenger molecules; and a number of metabolites.

• Cells interconnected through gap junctions are electrically coupled and generally act in a coordinated fashion (i.e., as a syncytium).

Gap junctions: connect the cytoplasm of adjacent cells; important in cardiac muscle and skin

3. Desmosomes (macula adherens)

• They are plaquelike areas of intermediate filaments that create strong contacts between cells, typically present on the lateral membrane of cells.

• Help resist shearing forces and therefore often found in squamous epithelium

Desmosomes: cell-to-cell spot adhesions present on lateral membrane of cells, which help resist shearing forces in squamous epithelium

F. Transport across membranes

1. Simple diffusion

• Diffusion of nonpolar and polar substances

a. Diffusion of nonpolar substances such as oxygen and carbon dioxide gases across a membrane is more rapid than the diffusion of polar substances such as water.

b. This is due to their relative solubility in lipids: nonpolar gases easily dissolve into the lipid bilayer, but water is insoluble because of its polarity.

Nonpolar substances such as gases easily diffuse across lipid bilayer

2. Osmosis

• Osmosis is the movement of water, not dissolved solutes, across a semipermeable membrane.

Osmosis: diffusion of water from high to lower concentration across semipermeable membrane

• A difference in solute concentration across the membrane generates osmotic pressure, which causes the movement of water from the area of low solute concentration (hypotonic solution) to that of high solute concentration (hypertonic solution) (Fig. 1-4).

Osmotic pressure: generated by solute concentration gradient across semipermeable membrane, promotes osmosis

• Osmotic pressure depends on the following:

a. The concentration of osmotically active particles

• Osmotic pressure increases with increased solute concentration.

b. The ability of these particles to cross the membrane, which depends on particle size and charge

• If the solutions on either side of the membrane have equal osmotic pressure, they are said to be isotonic.

3. Carrier-mediated transport (Table 1-5)

• Characteristics of carrier-mediated transport

a. Stereospecificity of carrier proteins

• Only one isomer of a substance is recognized by the carrier protein; for example, d-glucose but not l-glucose is transported by the GLUT4 transporters in muscle and the liver.

Stereospecificity of transport proteins: recognize only a single isomer of a substance

b. Competition for carrier binding sites

• Substances with similar structure can compete for binding to the carrier protein; for example, d-galactose binds to and is transported by the same GLUT4 transporter as d-glucose, thereby inhibiting the transport of glucose.

c. Saturation of carrier proteins

• When all of the transport binding sites for a particular substance are occupied, the transport maximum (T_m) has been reached; the substance can no longer bind to its carrier and therefore cannot pass through the membrane (Fig. 1-5).

Transport maximum: above this transport rate, the substance can no longer be transported into cells

• Facilitated transport (diffusion)

a. Occurs down an electrochemical gradient and therefore does not require metabolic energy

b. Stops if the concentration of the substance inside the cell reaches the extracellular concentration or if carrier molecules become saturated

c. For example, the GLUT4 transporter carries glucose into skeletal muscle and the liver; this proceeds for as long as a concentration gradient for glucose is present.

Facilitated transport: occurs down electrochemical gradient; requires carrier transport molecules

• Active transport

a. “Uphill” transport of a substance against its electrochemical gradient

b. Energy from hydrolysis of adenosine triphosphate (ATP) is required.

Active transport: transport against electrochemical gradient; energy provided by ATP hydrolysis

a. Secondary active transport

• The simultaneous movement of two substances across the cell membrane indirectly coupled to ATP hydrolysis

(1) One substance moves down its concentration gradient, and this drives the “uphill” transport of the other substance against its concentration gradient.

Secondary active transport: diffusion of substance down its concentration gradient drives the transport of other substance against its concentration gradient

• In cotransport (symport), both substances move in the same direction (e.g., Na⁺-glucose cotransport in the epithelial cells of the brush border of the small intestine).

Cotransport: both substances transported in same direction

• In countertransport (antiport), the substances move in opposite directions (e.g., the Na⁺-Ca²⁺ countertransporter of heart muscle cells moves Ca²⁺ against its concentration gradient as Na⁺ moves down its concentration gradient) (Fig. 1-6).

Countertransport: substances move in opposite directions

Pharmacology note: Cardiac glycosides such as ouabain and digitalis inhibit the Na⁺,K⁺-ATPase (sodium) pump in the myocardium (see Fig. 1-6). This increases the amount of sodium inside the cell, triggering the Ca²⁺-Na⁺ countertransporter. More calcium is brought into the cell, which increases the contraction of atrial and ventricular myocardium and increases cardiac output.