Escolar Documentos
Profissional Documentos
Cultura Documentos
E
very once in a while biologists come to the consequences can be dire indeed. Many of
realize that what was at one time regard- the millions of people who suffer from Crohn’s
ed as a minor and relatively obscure cel- disease, a form of inflammatory bowel disease,
lular process is, in fact, of central importance. may have defective autophagy systems that can-
Not only is the process ubiquitous, but by virtue not keep the microbial flora in the gut from
of that ubiquity it also plays a role in a broad growing uncontrollably. A breakdown in the
key concepts range of normal and disease states. So it was autophagy system in brain neurons has been
n Inside the cytoplasm of a with the discovery of the role of nitric oxide in linked to Alzheimer’s disease, as well as to ag-
living cell, organelles called the circulatory system, a discovery that led to a ing itself. Even a well-oiled autophagy system
autophagosomes continual Nobel Prize, as well as to many beneficial drugs. can be detrimental, enabling a cancer cell tar-
ly engulf bits of cytoplasm, Now another formerly obscure process known geted by a blast of radiation or a toxic dose of
along with damaged cell as autophagy is suddenly claiming extraordi- chemotherapy to survive and repair itself, there-
parts and invading bacteria
nary scientific attention. by perpetuating the cancer. Autophagy can
and viruses. The “sweep
In basic outline, autophagy (from the Greek, sometimes act to eliminate a diseased cell for
ings” are carried to diges
tive organelles for breakup meaning “self-eating”) is simple enough. With- the greater good of the organism, but it can also
and recycling. The process is in every cell but outside the nucleus lies the cy- become overzealous, consuming a cell even
called autophagy. toplasm, a kind of formless jelly supported by a when the loss of that cell is not in the interest of
skeletal matrix, in which a vast and intricate the organism.
n ell biologists are learning
C
population of large molecules, or macromole- In the past decade investigators have been
about autophagy in great
detail by tracing the protein cules, and specialized functional subunits called able to learn in great detail how the autophagy
signals that drive and organelles is suspended. The workings of the cy- system works. Such insights are important not
control the process. toplasm are so complex— rather like some of to- only because they enhance the basic under-
day’s computer systems — that it is constantly standing of how cells work, but also because
n fuller understanding of
A
becoming gummed up with the detritus of its they could lead to the design of drugs that
autophagy is opening up
new options for treating ongoing operations. Autophagy is, in part, a might induce the system to ramp up or qui-
cancer, infectious disease, cleanup process: the trash hauling that enables et down as needed. Controlling the
immune disorders and a cell whose cytoplasm is clotted with old bits rates of the process as well as the spe-
dementia, and it may one of protein and other unwanted sludge to be cific targets of its activities could
day even help to slow cleaned out. have enormous therapeutic benefits
down aging. Refurbishing the cytoplasm can give new life and might even alleviate some of
—The Editors to any cell, but it is particularly important to the decline in brain functioning peo-
cells such as neurons that do not get replaced. A ple experience as they age.
adam questell
scarce, autophagy intensifies; autophago- protein. Mitochondria, for instance, are the
somes scavenge the cytoplasm for proteins organelles primarily responsible for generat-
and organelles (regardless, it seems, of their ing energy within a cell, and they can send
functional status) that can be digested into signals to other parts of the cell that initiate
nutrients and energy the cell can use. apoptosis, or cellular suicide.
If autophagy evolved, in part, as a re- Cells induce apoptosis for a variety of rea-
sponse to starvation, its housekeeping func- sons, all more or less for the greater good of
tion— even when nutrients abound— has long the organism. For example, the body continu-
te
in
o
c yc times the usual release of ROS, much more than chemical building blocks that are
le
●
4 P ROTEIN RECYCLING: normal cellular detoxification systems can han- delivered to the cytoplasm as
The double-layered
membrane seals, and
dle. The escape of such large amounts of ROS nutrients. The nutrient scarcity
poses a cancer threat, because ROS that reach also signals the cell to reduce its
the resulting autophago
functioning volume (schematical-
some sheds membrane the nucleus may induce malignant changes in
proteins that took part ly portrayed here as shrinkage).
genes. Once again, autophagy can come to the Without such literal “self-eating,”
in its formation. The
proteins are cycled back rescue, removing the dysfunctional mitochon- the essential activities of the cell
into the cytoplasm dria from the cell. Eileen White of Rutgers Uni- could not continue and the cell
versity believes that autophagy also mitigates would die.
Autophagosome
genome damage in cancer cells, thereby helping Healthy cell
to prevent new tumors from forming.
Autophagosome
ally generates more cells than it needs, and they
Cell
must be eliminated. An aging cell that has ceased Double-Edged Sword
functioning efficiently may kill itself to make Soon after cell biologists unraveled the intricate
room for younger, more robust cells. A cell that molecular pathways of apoptosis, they recog-
switches from normal growth to cancerous pro- nized that cells can kill themselves by other
liferation can also be induced to commit suicide, means as well. Autophagy became a prime sus-
making apoptosis one of the most important pect. Current nomenclature reflects that histo-
built-in barriers against cancer. Apoptosis de- ry: apoptosis is also known as programmed cell
Organelles
pends on a complex series of cellular events, rig- death type I; autophagy is sometimes referred Macromolecules
orously orchestrated by numerous protein sig- to as programmed cell death type II — although
nals, and so the death of the cell by apoptosis is that designation remains controversial. Nutrient-deprived cell
considered to be a programmed event. Autophagy could lead to cell death in two Extra autophagosomes
But a faulty mitochondrion can wreak havoc ways: the process might simply continue digest- Reduced volume
if it sets off apoptosis at the wrong time [see box ing the contents of the cytoplasm until the
on next page]. Among the by-products of a cell dies, or it may stimulate apoptosis. But
functioning mitochondrion are reactive oxygen why would a process that often prevents un-
species (ROS) — oxygen ions and other oxygen- timely cell death from accidental apoptosis
based molecular fragments. Working with such sometimes be invoked to cause cell death itself?
jen christiansen
volatile chemicals often causes mitochondria to The puzzle may turn out to have a fascinating
leak some of their contents, including the signal- resolution. Apoptosis and autophagy may be
ing proteins that initiate apoptosis. In other closely interrelated and carefully balanced. For
w w w. S c i A m . c o m SC
© 20 08 SCIENTIFIC AMERIC AN, INC. I ENT I F I C A M E R I C A N 77
[LIVE OR LET DIE?]
example, if organelle damage is too extensive Atg5, which plays a leading role in the forma-
for autophagy to bring under control, the cell tion of autophagosomes, can make its way to
must die for the sake of the entire organism. The mitochondria. Once there Atg5 can switch what
cell may then rely on either of its suicide pro- was initially a purely autophagic response to an
grams: it may allow autophagy to continue to apoptotic one.
the end, or it can signal for apoptosis, holding Every benefit seems to have its flaws, and au-
autophagy as a backup system if apoptosis is tophagy is no exception. We noted earlier that
compromised. Two of the most intense and cancer cells can sometimes invoke autophagy to
somewhat controversial areas of current inves- save themselves. Anticancer treatments are of-
tigation are how autophagy and apoptosis inter- ten aimed at inducing malignant cells to commit
connect and whether autophagy on its own suicide. Yet some cancer cells can defend against
should be considered a pathway for cell death. the treatments because autophagy jumps in to
Work at the molecular level may help resolve remove damaged mitochondria before they can
whether autophagy is primarily a pathway for trigger apoptosis. In fact, radiation and chemo-
cell survival or whether it can, in addition, act therapy can actually induce higher-than-usual
as an “angel of death.” Recent studies by Beth levels of autophagy.
Levine of the University of Texas Southwestern Cancer cells can also take advantage of auto
Medical Center at Dallas and Guido Kroemer phagy to avoid being starved. Few nutrients can
of the French National Scientific Research Cen- reach the inside of a tumor, but as we men-
Does autophagy ter (CNRS) have shown how the two processes tioned earlier, a shortage of nutrients can trig-
can be coordinated. One of the proteins that sig- ger autophagy, prolonging the life of a cancer
contribute nals for autophagy to begin, known as Beclin 1, cell by enabling it to break down its own mac-
mainly to cell binds with a protein that prevents apoptosis romolecules for food. A straightforward treat-
from starting, Bcl-2. Life-and-death decisions ment strategy might therefore be to suppress
survival—or are made as bonds between the two kinds of autophagy within a tumor or during radiation
does it also act proteins are enhanced or broken. Levine’s find- therapy or chemotherapy. Drugs for that pur-
jen christiansen
ings of that connection between autophagy and pose are in clinical trials. Unfortunately, as
as an “angel apoptosis have been further supported by the White points out, suppressing autophagy could
of death”? discovery that a fragment of a protein known as boost the number of genetic mutations in can-
lead to neuron damage. But the latest research leading to a buildup of damaged proteins and consequent swelling in a neurite, or pro
shows, tellingly, that enzymes that help to de- jection from the cell body of the neuron. The immature autophagosomes collect at the
posit the plaques in certain early-onset forms of same site. Enzymes (yellow) that create protein fragments called amyloid beta seem to
Alzheimer’s are present on the membranes of concentrate on the immature autophagosomes, and those fragments collect on the out
er neurite surface (orange). Aggregates of amyloid beta are the so-called senile
autophagosomes. According to Nixon, such
plaques characteristic of neurons in the brains of Alzheimer’s patients. Together those
plaques may stem in part from incomplete auto
findings suggest that a breakdown in autophagy may contribute to Alzheimer’s disease.
phagy and the consequent failure of the neurons
to digest substances that would normally be Buildup of damaged proteins Enzyme that creates
swept up from their cytoplasm, broken down from incomplete autophagy amyloid beta
and recycled for parts [see box at right]. Sup- Immature Senile plaques
autophagosome
porting Nixon’s conclusion, electron micro-
graphs of senile plaques in the brains of Alz
heimer’s patients show massive numbers of im-
mature autophagosomes accumulating inside
the parts of the neurons nearest the plaques.
Precisely how the plaque material may collect
on the outside of nerve cells has not been con-
clusively traced. Neuron Swollen neurite
Given those results, it would seem that any
w w w. S c i A m . c o m SC I ENT I F I C A M E R I C A N 79
© 20 08 SCIENTIFIC AMERIC AN, INC.
Mycobacterium tuberculosis, the tuberculosis
bacterium annually responsible for two million
Some micro long functioned as a major barrier to invasion
by pathogens and their replication in human
deaths worldwide; gut pathogens such as Shi organisms have cells — a barrier that disease-causing agents
gella and Salmonella; group A streptococci;
Listeria, which occurs in raw-milk cheeses;
learned to must overcome to survive. Not surprisingly,
HIV is another good example of a pathogen that
Francisella tularensis, which the Centers for subvert auto can harness autophagy for its own purposes.
Disease Control and Prevention has listed as a
bioterrorism agent; and parasites such as Toxo
phagy. HIV can Two groups in France, one led by Martine
Biard-Piechaczyk of the Center for Studies of
plasma gondii, which is a major cause of illness even accelerate Pathogenic Agents and Biotechnologies for
in people with AIDS.
Yet just as cancer cells can exploit autophagy
the process in Health and the other by Patrice Codogno of
I NSERM, have jointly shown that HIV, which
for their own survival, some microorganisms neighboring infects immune system cells known as CD4+ T
have evolved ways to subvert the process. For
example, Legionella pneumophila, which
immune system cells, can increase cell death in uninfected “by-
stander” cells of the same kind. As HIV enters
causes Legionnaires’ disease, is a bacterium cells, causing a cell, it sheds its outer envelope, and the protein
that readily gets inside a cell. But if L. pneumo
phila bacteria are engulfed by an autophago-
them to commit that makes up the envelope induces uncon-
trolled, excess autophagy and then apoptosis in
some, they can delay or even prevent the au- suicide. cells that surround the HIV-infected cell. Thus
tophagosome from fusing with a lysosome. by activating autophagy in “innocent” bystand-
Thus instead of serving as a vehicle that helps to er cells, HIV further reduces the number of
rid the cell of a pathogen, the infected organelle healthy CD4+ T cells in the body. Eventually the
becomes a niche where the bacteria can repli- catastrophic loss of immune system cells brings
cate, using the sequestered cytoplasm as a nutri- about full-blown AIDS.
ent supply.
The very existence of such clever evolution- The Immune Connection
ary tactics is good evidence that autophagy has Autophagy not only eliminates pathogens
directly; investigators have also found that it
[CELL DEFENSE] takes part in immune responses [see box below].
REPELLING INVADERS For example, autophagosomes help to deliver
pathogens or pathogen products to membrane
Autophagy can mount several kinds of defenses against pathogens that enter the molecules called toll-like receptors (TLRs), a
cytoplasm. The diagram shows how they can operate. subset of the regulators that control the so-
called innate immune response. The role of
pathogen degradation innate immune response
autophagosomes in the process is to make a
Vesicle that buds off the cell ●
1 V
irus that evades the first line of autophagosome clever “topological” inversion. A pathogen in
membrane with an invading defenses releases its nucleic acid (RNA, for instance)
the cytoplasm can hide from TLRs because
microorganism inside can be Virus
“swallowed whole” by an TLR binding sites for pathogens
autophagosome and digested
Cell membrane ●
3 V
iral RNA in the
into harmless fragments endosome binds with Protein
by a lysosome Toll-like a TLR, stimulating fragments
receptor (TLR) production of more (antigens)
Bacterium autophagosomes
Endosome and interferon (an
Viral “innate” response)
jen christiansen
protein Autophagosome
that can interfere
coat
with viral replication ●
6 A
fragment
of viral protein
Endosome is loaded onto an
Phagophore
Viral ●
2 A
n autophago MHC II molecule
RNA some delivers and presented at the
some of the viral cell surface, triggering
Vesicle RNA to an endo a specific “adaptive”
Phagophore some, or compart Signal immune response
ment in the cell Antigen- against cells infected
presenting
Lysosome Autophagosome ●
4 The cell trans
Activated molecule
(MHC II)
with the virus
lates some of interferon
the remaining gene
viral RNA into
●
5 A n autophagosome delivers viral
protein to another kind of endosome,
Enzymes viral protein where the protein is broken up
Nucleus
Viral protein Interferon
adaptive immune response
© 2008 SCIENTIFIC AMERIC AN, INC.
[autophagy in medicine]
face away from the cytoplasm. The binding sites
point either toward the space outside the cell or NEW WEAPONS AGAINST DISEASE
toward the inside of an endosome, or intracel- Intensifying, suppressing or otherwise manipulating autophagy in specific kinds
lular compartment. But autophagosomes can of cells could become a powerful part of the medical arsenal. Here are just a few
fix this topological problem by scooping up examples of the potential treatment options.
pathogens or their parts from the cytoplasm
and delivering them to an endosome that disease strategy goals
embeds TLRs in its membrane. There the patho-
Cancer Inhibit autophagy Help to prevent tumor cells from consuming the
gen molecules meet TLRs at last. Their encoun-
in cells of cancer- contents of their own cytoplasm, thereby surviving
ter signals the cell to produce chemicals called ous tumors in oxygen- or nutrient-starved environments
interferons, which act, for instance, to suppress
the replication of the pathogen. This innate Cancer Enhance Lower the chances that mutations and secondary
immune response is generated to combat infec- autophagy in cells tumors will arise when too little autophagy enables
at risk of cancer DNA-damaging molecules to accumulate in the cell
tion as soon as it starts — no time is needed for
the cell to build a highly specific response to the Huntington’s Enhance autopha- Help to remove toxic microaggregates of proteins
pathogen. disease gy with drug rapa- that accumulate in nerve cells
But autophagosomes can also help build that mycin (sirolimus)
highly specific immune response, known as
Tuberculosis Enhance Kill disease-causing agents that hide in the cyto-
adaptive immunity. For example, when a virus autophagy plasm, both in people who are sick and in carriers
invades the cytoplasm and tricks the cell into who are symptom-free
making viral protein, an autophagosome en-
gulfs some of the viral protein and ushers it into If inefficient autophagy is to blame, Cuervo
another kind of endosome that embeds so- says, that could help explain why caloric restric-
called MHC class II molecules in its membrane. tion has been found to extend average life spans
Once inside that endosome, the viral protein is in several kinds of experimental animals. The
partly broken up, and a piece of it is loaded onto less food such animals eat (provided they get an
a part of an MHC class II molecule that faces adequate supply of essential nutrients), the lon-
the inside of the endosome. (Just as with the ger they live, and the same may be the case for
TLR, the MHC class II molecule would not people. Recall that a restricted food supply— in-
meet properly with the pathogen molecule if the cipient starvation— speeds up autophagy. Hence,
autophagosome did not bring the pathogen mol- caloric restriction as one ages might offset the
ecule inside the endosome.) Once the MHC natural age-related decline of autophagy and so
class II molecule is bound to the pathogen frag- prolong the essential housekeeping function of
ment and the assemblage is transported to the the process in cells. Furthermore, Cuervo adds, ➥ more to
surface of the cell, the immune system begins recent research shows that if you can prevent explore
mounting an adaptive immune response, a slow- the decline of autophagy in experimental ani-
Cell Suicide in Health and Disease.
er but far more specific and more efficient re- mals, you can often avoid the usual age-related
Richard C. Duke, David M. Ojcius
sponse than innate immunity can muster. buildup of proteins damaged by reactions with and John Ding-E Young in Scientific
oxygen compounds. American, Vol. 275, pages 80–87;
Long Life? What was once seen primarily as a hedge December 1996.
Remarkably, autophagy may also play a role in against cellular starvation has come to be rec-
Autophagy in Health and Disease:
determining the human life span. Most people ognized as central to a broad range of factors
A Double-Edged Sword. T. Shintani
take it for granted that many diseases become affecting human health and disease. Research and D. J. Klionsky in Science, Vol.
more frequent with age, including cancer and into autophagy is expanding in new and unex- 306, pages 990–995; November 5,
the degeneration of neurons. The reason, in pected directions, generating an exponentially 2004.
part, may be a decline in the efficiency of auto increasing body of scientific knowledge. But we
Autophagy in Immunity and Infec-
phagy. According to Ana Maria Cuervo of the have only begun. Learning to promote or inhib-
tion: A Novel Immune Effector.
Albert Einstein College of Medicine, the current it autophagy at will holds great promise for the Edited by Vojo Deretic. Wiley-VCH,
thinking is that cellular systems, including treatment of disease and perhaps even for slow- 2006.
autophagy, undergo a steady loss of function ing down the natural process of aging. But
with age. In particular, the systems that remove whether autophagy can be harnessed to benefit Potential Therapeutic Applica-
tions of Autophagy. D. C. Rubinsz
aberrant or dysfunctional proteins and organ- health, much less to become the elusive fountain
tein, J. E. Gestwicki, L. O. Murphy
elles begin to work less efficiently, and the of youth, will depend on gaining a fuller under- and D. J. Klionsky in Nature
resulting buildup of damaged cellular compo- standing of its mechanisms and of the intricate Reviews Drug Discovery, Vol. 6,
nents leads to disease. biochemical signals on which it depends. n pages 304–312; April 2007.
w w w. S c i A m . c o m SC
© 20 08 SCIENTIFIC AMERIC AN, INC. I ENT I F I C A M E R I C A N 81