Interactions among organelles

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Interactions among Organelles
Organelles are involved in important cellular processes, such as the uptake and release of
material by cells, protein synthesis, and intracellular digestion. These interactions provide the
basis for a functional approach to the dynamics of cell biology.
A. Uptake and release of material by cells
 Endocytosis is the uptake (internalization) of material by cells. Endocytosis includes
pinocytosis, receptor-mediated endocytosis, and phagocytosis.
o Pinocytosis ("cell drinking") is the nonspecific (random) uptake of extracellular fluid
and material in solution into pinocytic vesicles.
o Receptor-mediated endocytosis is the specific uptake of a substance [e.g., low-
density lipoproteins (LDLs) and protein hormones] by a cell that has a plasma-
membrane receptor for that substance (which is termed a ligand). It involves the
following sequence of events
 A ligand binds specifically to its receptors on the cell surface.
 Ligand-receptor complexes cluster into a clathrin-coated pit,which invaginates and
gives rise to a clathrin-coated vesicle containing the ligand.
 The cytoplasmic clathrin coat is rapidly lost, leaving an uncoated endocytic vesicle
containing the ligand.
o Phagocytosis ("cell eating") is the uptake of microorganisms, other cells, and
particulate matter (frequently of foreign origin) by a cell. Phagocytosis usually involves
cell-surface receptors. It is characteristic of cells—particularly macrophages—that
degrade proteins and cellular debris and involves the following sequence of events:
 A macrophage binds, via its Fc receptors, to an antibody-coated [immunoglobulin
G (IgG)-coated] bacterium, or via its C3b receptors to a complement-coated
bacterium.
 Binding progresses until the plasma membrane completely envelops the
bacterium, forming a phagocytic vacuole.
 Exocytosis is the release of material from the cell via fusion of a secretory granule
membrane with the plasma membrane. It requires interaction of receptors in both the
granule and plasma membrane, as well as adherence and joining of the two phospholipid
membrane bilayers. Exocytosis takes place in both regulated and constitutive secretion.
 Regulated secretion (signal directed) is the release, in response to an
extracellular signal, of proteins and other materials stored in the cell.
 Constitutive secretion (default pathway) is the more-or-less continuous release of
material (e.g., collagen and serum proteins) without any intermediate storage step.
An extracellular signal is not required for constitutive secretion.
 Membrane recycling maintains a relatively constant plasma-membrane surface area
following exocytosis. In this process, the secretory granule membrane added to the
plasma-membrane surface during exocytosis is retrieved during endocytosis via clathrin-
coated vesicles. This vesicular membrane is returned to the TGN (via early endosomes)
for recycling.

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B. Protein synthesis
1. Synthesis of membrane-packaged proteins involves translation of mRNAs encoding
secretory, membrane, and lysosomal proteins on ribosomes at the surface of the RER;
transport of the growing polypeptide chain across the RER membrane and into the cisterna;
and its processing within the RER.
o Transport of newly formed peptide into the RER cisterna is thought to occur by a
mechanism described by the signal hypothesis as follows:
 mRNAs for secretory, membrane, and lysosomal proteins contain codons that
encode a signal sequence.
 When the signal sequence is formed on the ribosome, a signal recognition
particle (SRP) present in the cytosol binds to it.
 Synthesis of the growing chain stops until the SRP facilitates the relocation of the
polysome to SRP receptors in the RER membrane.
 The large subunits of the ribosomes interact with ribosome receptor proteins,
which "bind" them to the RER membrane. The SRP detaches, and multisubunit
protein translocators form a pore across the RER membrane. Synthesis resumes,
and the newly formed polypeptide is threaded through the pore and into the RER
cisterna (lumen).

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o Posttranslational modification in the RER
After the newly formed polypeptide enters the cisterna, a signal peptidase cleaves the signal
sequence from it. The polypeptide is glycosylated. Disulfide bonds form, converting the linear
polypeptide into a globular form.
o Protein transport from the RER to the ERGIC
 Transitional elements of the RER give rise to coatomer coated vesicles
containing newly synthesized protein.
 These vesicles move to the ERGIC, where they deliver the protein.
 The ERGIC is the first recycling compartment in the secretory pathway. Proteins
either move forward toward the CGN, or (if they are RER-resident proteins) they
are captured by a specific membrane receptor protein and returned in coatomer
vesicles to the RER along a microtubule-guided pathway.
o Anterograde transport from the ERGIC to the CGN (cis Golgi) is via coatomer
coated vesicles.
o Movement of material anterograde among the Golgi subcompartments may occur
by cisternal maturation and/or by vesicular transport as follows:
 Cisternae containing proteins may change in biochemical composition as they
move intact across the stack.
 COP-II-coated vesicles may bud off of one cisterna and fuse with the dilated rim
of another cisterna.
 Although both of the above mechanisms have been observed, the precise way
that anterograde transport occurs across the Golgi stack of cisternae is currently
unresolved.
 Retrograde vesicular transport occurs between Golgi cisternae and between the
Golgi and the ERGIC or RER via coated vesicles.
o Protein processing in the Golgi complex occurs as proteins move from the cis to
the trans face of the Golgi complex through distinct cisternal subcompartments. Protein
processing may include the following events, each of which occurs in a different
cisternal subcompartment:

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 Proteins targeted for lysosomes are tagged with mannose 6-phosphate in the
CGN.
 Mannose residues are removed in cis and medial cisternae.
 Terminal glycosylation of some proteins with sialic acid residues and galactose
occurs.
 Sulfation and phosphorylation of amino acid residues takes place.
 A membrane similar in composition and thickness to the plasma membrane is
acquired.
o Sorting of proteins in TGN
 Regulated secretory proteins are sorted from membrane and lysosomal proteins
and delivered via clathrin-coated vesicles to condensing vacuoles, where removal
of water, via ionic exchanges, yields secretory granules.
 Lysosomal proteins are sorted into clathrin-coated regions of the TGN that have
receptors for mannose 6-phosphate, and are delivered to late endosomes via
clathrin-coated vesicles.
 Plasma-membrane proteins are sorted into coatomer-coated regions of the TGN
and delivered to the plasma membrane in coatomer-coated vesicles.
Synthesis of cytosolic proteins takes place on polyribosomes free in the cytosol and is
directed by mRNAs that lack signal codons. The proteins (e.g., protein kinase and hemoglobin)
are released directly into the cytosol.

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C. Intracellular digestion
o Nonlysosomal digestion is the degradation of cytosolic constituents by mechanisms
outside of the vacuolar lysosomal pathway. The major site for the degradation of
unwanted proteins is the proteosome, a cylindrical complex of nonlysosomal
proteases. Proteins marked for destruction are enzymatically tagged with ubiquitin,
which delivers them to the proteosome, where they are broken down to small peptides.
o Lysosomal digestion (see Figure 3.4) is the degradation of material within various
types of lysosomes by lysosomal enzymes. Different lysosomal compartments are
involved, depending on the origin of the material to be degraded.
 Heterophagy is the ingestion and degradation of foreign material taken into the
cell by receptor-mediated endocytosis or phagocytosis.
 Digestion of endocytosed ligands occurs in multivesicular bodies
 Digestion of phagocytosed microorganisms and foreign particles begins
and may be completed in phagolysosomes.
 Autophagy is the segregation of an organelle or other cell constituents within
membranes from the RER to form an autophagic vacuole, which is subsequently
digested in an autophagolysosome.
 Crinophagy is the fusion of hormone secretory granules with lysosomes and their
subsequent digestion. Crinophagy is used to remove excess numbers of secretory
granules from the cell.
Clinical Considerations
Lysosomal storage diseases are hereditary conditions in which the synthesis of
specific lysosomal acid hydrolases is impaired. They are characterized by the inability of
lysosomes to degrade certain compounds, which accumulate and interfere with cell
functioning.
o In Tay-Sachs disease, glycolipids accumulate in neurons.
o In glycogen storage disease, glycogen is abundant in the liver and muscle.
o In Hurler syndrome, glycosaminoglycans accumulate in many tissues and organs.
Familial hypercholesterolemia is associated with a decreased ability of cells to take in
cholesterol, which normally is ingested by receptor-mediated endocytosis of LDLs.
o This disease is caused by an inherited genetic defect that results in an inability to
synthesize LDL receptors, or in the synthesis of defective receptors unable to
bind either to LDLs or to clathrin-coated pits.
o It is characterized by an elevated level of cholesterol in the bloodstream, which
facilitates early development of atherosclerosis, which may be fatal.
Peroxisomal diseases
o Zellweger syndrome is a genetic disease in which normal peroxisomes are
absent. Infants with this syndrome have profound neurological, liver, and kidney
problems and usually die within a few months. Electron micrographs of biopsies
from these patients reveal empty peroxisomes, lacking enzymes. Although
peroxisomal enzymes may be synthesized, they become mislocated in the
cytosol.
o Adrenoleukodystrophy is caused by the inability of peroxisomes to metabolize
fatty acids. Therefore, lipids accumulate in the nervous system and adrenal
glands, impairing their function.