CHAPTER 2
Overview of Cellular Physiology in Medical Physiology 35rest of the cytoplasm, and external material such as endocy-
tosed bacteria, as well as worn-out cell components, are di-
gested in them. The interior is kept acidic by the action of a
proton pump,
or
H
- , ATPase.
This integral membrane pro-
tein uses the energy of ATP to move protons from the cytosol
up their electrochemical gradient and keep the lysosome rela-
tively acidic, near pH 5.0. Lysosomes can contain over 40 types
of hydrolytic enzymes, some of which are listed in Table 2–1.
Not surprisingly, these enzymes are all acid hydrolases, in that
they function best at the acidic pH of the lysosomal compart-
ment. This can be a safety feature for the cell; if the lysosome
were to break open and release its contents, the enzymes
would not be efficient at the near neutral cytosolic pH (7.2),
and thus would be unable to digest cytosolic enzymes they
may encounter. Diseases associated with lysosomal dysfunc-
tion are discussed in Clinical Box 2–1.
PEROXISOMES
Peroxisomes are 0.5
μ
m in diameter, are surrounded by a
membrane, and contain enzymes that can either produce
H
2
O
2
(oxidases)
or break it down
(catalases).
Proteins are di-
rected to the peroxisome by a unique signal sequence with the
help of protein chaperones,
peroxins.
The peroxisome mem-
brane contains a number of peroxisome-specific proteins that
are concerned with transport of substances into and out of the
matrix of the peroxisome. The matrix contains more than 40
enzymes, which operate in concert with enzymes outside the
peroxisome to catalyze a variety of anabolic and catabolic re-
actions (eg, breakdown of lipids). Peroxisomes can form by
budding of endoplasmic reticulum, or by division. A number
of synthetic compounds were found to cause proliferation of
peroxisomes by acting on receptors in the nuclei of cells. These
peroxisome proliferation activated receptors (PPARs)
are
members of the nuclear receptor superfamily. When activat-
ed, they bind to DNA, producing changes in the production of
mRNAs. The known effects for PPARs are extensive and can
affect most tissues and organs.
CYTOSKELETON
All cells have a
cytoskeleton,
a system of fibers that not only
maintains the structure of the cell but also permits it to change
shape and move. The cytoskeleton is made up primarily of
mi-
crotubules, intermediate filaments,
and
microfilaments
(Figure 2–5), along with proteins that anchor them and tie
them together. In addition, proteins and organelles move
along microtubules and microfilaments from one part of the
cell to another, propelled by molecular motors.
Microtubules
(Figures 2–5 and 2–6) are long, hollow struc-
tures with 5-nm walls surrounding a cavity 15 nm in diame-
ter. They are made up of two globular protein subunits:
α- and
β
-tubulin. A third subunit,
γ
-tubulin, is associated with
the production of microtubules by the centrosomes. The
α
and
β
subunits form heterodimers, which aggregate to form
long tubes made up of stacked rings, with each ring usually
containing 13 subunits. The tubules interact with GTP to
facilitate their formation. Although microtubule subunits can
be added to either end, microtubules are polar with assembly
predominating at the “+” end and disassembly predominating
at the “–” end. Both processes occur simultaneously in vitro.
The growth of microtubules is temperature sensitive (disas-
sembly is favored under cold conditions) as well as under the
control of a variety of cellular factors that can directly interact
with microtubules in the cell.
Because of their constant assembly and disassembly, micro-
tubules are a dynamic portion of the cell skeleton. They provide
the tracks along which several different molecular motors move
transport vesicles, organelles such as secretory granules, and
mitochondria, from one part of the cell to another. They also
form the spindle, which moves the chromosomes in mitosis.
Cargo can be transported in either direction on microtubules.
There are several drugs available that disrupt cellular func-
tion through interaction with microtubules. Microtubule
assembly is prevented by colchicine and vinblastine. The anti-
cancer drug
paclitaxel (Taxol)
binds to microtubules and
TABLE 2–1
Some of the enzymes found in lysosomes
and the cell components that are their substrates.
Enzyme Substrate
Ribonuclease RNA
Deoxyribonuclease DNA
Phosphatase Phosphate esters
Glycosidases Complex carbohydrates; glycosides and
polysaccharides
Arylsulfatases Sulfate esters
Collagenase Collagens
Cathepsins ProteinsCLINICAL BOX 2–1
Lysosomal Diseases
When a lysosomal enzyme is congenitally absent, the lyso-
somes become engorged with the material the enzyme
normally degrades. This eventually leads to one of the
lyso-
somal storage diseases.
For example,
α
-galactosidase A
deficiency causes Fabry disease, and
β
-galactocerebrosi-
dase deficiency causes Gaucher disease. These diseases are
rare, but they are serious and can be fatal. Another example
is the lysosomal storage disease called Tay–Sachs disease,
which causes mental retardation and blindness. Tay–Sachs
is caused by the loss of hexosaminidase A, a lysosomal en-
zyme that catalyzes the biodegradation of gangliosides
(fatty acid derivatives).