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Programmed cell death targets discovered
Apoptotic processes, i.e. cell death mediated by intracellular programmes, have been
implicated in a variety of diseases. Apoptotic processes eliminate superfluous or irreparably
damaged cells from the body; however, defective apoptotic processes harm the organism.
New research results show that processes at the mitochondrial membrane might be
excellent targets for pharmaceutical interference with apoptosis.
Apoptosis is a natural, controlled suicide
programme in multicellular organisms that
eliminates cells which would otherwise be
harmful to the body, such as extremely
damaged or old cells. Biochemical reaction
cascades lead to cell changes and death.
Cellular waste can be removed by
macrophages or other immune system cells. A
key step in apoptosis is the mitochondrial
release of the pro-apoptotic factor cytochrome
C into the cytoplasm where cytochrome C can
interact with factors different from the ones
found in the mitochondria. If this interaction
occurs, programmed cell death cannot be
stopped. Manipulating the release of
cytochrome C into the cytoplasm would,
therefore, be a perfect medical target. On the
one hand, targeting this particular process
would prevent the passage of cytochrome C in
cases where apoptosis is erroneously induced
due to disease. On the other hand, in diseases
such as cancer where apoptosis is suppressed,
enabling abnormal cells to multiply and
damage the entire organism, a drug to drive
abnormal cells into apoptosis would be
welcome.
A team of scientists from Tübingen led by Prof.
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Prof. Dr. Ana J. García-Sáez, who is of Spanish origin, has
Dr. Ana J. García-Sáez has managed to
held a professorship at the Interfaculty Institute of
elucidate the mechanism of cytochrome C
Biochemistry at the University of Tübingen (IFIB) since
release and identify targets for therapeutic
2013. © Jörg Abendroth / MPI for Developmental
interventions. García-Sáez carries out research Biology
work at the IFIB (Interfaculty Institute of
Biochemistry) at the University of Tübingen as
well as at the Max Planck Institute for Intelligent Systems in Tübingen. She has been working
on the biophysics of membranes and protein-membrane interactions for many years. Her latest
results were obtained thanks to a European Research Council (ERC) Starting Grant of around
1.4 million euros, which she was awarded in 2012. The funding period will end in 2017.
The formation of membrane pores is crucial for apoptosis
García-Sáez works with artificial membrane systems in which a single lipid bilayer rests on a glass support. Bax
proteins migrate into the membrane where they aggregate into pores that are large enough for the pro-apoptotic
factor cytochrome C to pass through. © Katia Cosentino, IFIB University of Tübingen
The release of cytochrome C into the cytoplasm relies on pore formation in the outer
mitochondrial membrane. Bcl-2 proteins are key in this process, in particular, a protein called
Bax. García-Sáez and her team used artificial membrane systems to show that Bax proteins
are integrated into the membrane as monomers, thereby forming pores. "We produced human
Bax proteins in bacteria and added them to synthetic mitochondrial membranes," says GarcíaSáez "The proteins mostly assemble into dimers in the membranes, but we have also found
tetramers and hexamers. We also assume that octamers and decamers are produced, but they
are difficult to detect. The size of the pores in our artificial membrane system is highly variable
and changes with the amount of Bax proteins added. The more Bax proteins present in the
membrane, the larger the pores," says García-Sáez.
Mitochondria are surrounded by two membranes; Bax proteins are found in the outer
membrane. The pores are not very selective and the theoretical possibility exists that other
molecules could also pass through the membranes. Equally feasible is that proteins could be
transported in the opposite direction. It is still unclear what this implies for apoptosis. GarcíaSáez explains: "Mitochondria undergo major changes during apoptosis, but these processes are
not yet fully understood." The exact role of the membrane in the oligomerisation of the Bax
proteins and hence the initiation of pore formation also needs to be explored. It is, however,
clear that pore formation is controlled by proteins belonging to the Bcl-2 family. And this is
where medical applications could be possible.
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García-Sáez has managed to identify proteins that promote the aggregation of Bax proteins
and others that prevent the formation of Bax oligomers. "In healthy cells, inactive Bax
monomers are found in the cytoplasm. We have been able to show that cBid, which is another
protein from the Bcl-2 family, has no influence on the oligomerisation process. The protein BclxL can inhibit Bax by breaking Bax oligomers into di- and monomers," says García-Sáez. Even
though many details are not yet understood, the researchers' work will contribute to the
development of molecules that inhibit or promote the oligomerisation of Bax proteins and
hence pore formation, which would then interfere with apoptotic processes. Other researchers
have shown that small peptides derived from Bax or Bcl-2 domains are able to induce the
permeabilisation of membranes and hence apoptosis.
Drugs can be derived from regulatory proteins
Schematic drawing of what happens at the outer mitochondrial membrane: cBid and Bax belong to the same
protein family. cBid can activate Bax monomers at the outer mitochondrial membrane. The monomers are then
integrated into the membrane where they form dimers. Dimers can aggregate into larger Bax oligomers and
generate different sized pores. © Katia Cosentino, IFIB University of Tübingen
This knowledge is potentially groundbreaking for the development of therapeutic substances.
"However, the metabolic processes involved in pore formation and the induction of apoptosis
are nevertheless far more complicated than initially expected. Although some small molecules
are already being tested in clinical trials, it is difficult to develop molecules that target
specifically diseased cells," says García-Sáez. García-Sáez nevertheless believes one day
apoptotic processes will be controlled with small molecules that target pore formation.
"Theoretically, such molecules have the potential to treat all diseases that result from defective
apoptotic processes, including cancer, neurodegenerative diseases and cardiac infarction,"
García-Sáez who, together with her team, will continue to elucidate the fundamental
mechanisms and control processes of pore formation in order to create the necessary basis for
developing such proteins.
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Article
08-Dec-2015
leh
BioRegio STERN
© BIOPRO Baden-Württemberg GmbH
Further information
Prof. Dr. Ana J. García-Sáez
Tel.: +49 (0)7071 29-73318
E-mail: ana.garcia(at)uni-tuebingen.de
IFIB - Interfaculty Institute of
Biochemistry
The article is part of the following dossiers
Membrane proteins
apoptosis
basic
research
membrane proteins
mitochondria
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