Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

FMP and MDC Researchers Identify a Fundamental Process in Lysosomal Function and Protein Degradation

16.06.2010
The degradation of proteins and other macromolecules in cells is vital to survival. Disruption of this process can result in serious disease.

The research group of Professor Thomas Jentsch (Leibniz Institute for Molecular Pharmacology, FMP/ Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch) has now succeeded in identifying an essential cellular process necessary for the transport and degradation of macromolecules in endosomes and lysosomes, respectively. In two studies published in the same issue of Science, they showed that contrary to scientific consensus the function of these cell organelles not only depends on the pH, but also on chloride ion accumulation in their interior.*

Proteins are the building blocks and machines of life. Tens of thousands of them are present in each cell, where they perform essential tasks for the organism. Once they have fulfilled their function, they must be degraded to avoid causing damage. One way in which proteins can be degraded is via the digestion processes inside tiny cellular organelles, the lysosomes. The transport of the proteins destined for degradation to these cellular “trash bins” is partly carried out by endosomes, which deliver proteins from the cell surface to the cell interior.

The functionality of both endosomes and lysosomes depends on the ion concentration within their membrane-enclosed interior. In particular, an important role is ascribed to a high concentration of hydrogen ions, i.e. an acidic pH, inside those organelles.

The two studies by Dr. Stefanie Weinert, Dr. Gaia Novarino and Professor Thomas Jentsch focus on two ion transport proteins, the chloride transporters ClC-5 and ClC-7. These are located in the membrane of endosomes and/or lysosomes and exchange negatively charged chloride ions for positively charged hydrogen ions (protons).

ClC-5 is located in the membrane of endosomes in renal cells. If ClC-5 is defective or lacking altogether, proteins can hardly be absorbed from the urine any longer. In a cascade of indirect mechanisms, this leads to the development of kidney stones in Dent’s disease.

ClC-7 is located in the membrane of lysosomes in all cells of the body. The research group by Thomas Jentsch showed already a few years ago that mutations of ClC-7 in mice and humans lead to severe disease symptoms. Impaired lysosomal function in the brain results in severe degenerative changes that leads to massive neuronal death. A dysfunction of bone-degrading osteoclasts causes an excessive calcification of bones (osteopetrosis).

The chloride-proton exchangers ClC-5 and ClC-7 function parallel to proton pumps, which ensures an acidic environment within endosomes and lysosomes. ClC-5 and ClC-7 transport chloride ions into these organelles, thereby electrically balancing the inward transport of positively charged protons through the “pump”. Hitherto researchers had assumed that maintaining the charge balance was the sole task of ClC-5 and ClC-7, without which both the transport of endosomes and lysosomal protein degradation are impaired.

However, Professor Jentsch and his team showed several years ago that the pH in lysosomes devoid of ClC-7 is normal and that nevertheless lysosomal storage disease and osteopetrosis ensue. This means that charge balancing in lysosomes may involve a different, previously unknown mechanism, and that the main task of ClC-7 may rather be the regulation of lysosomal chloride concentration. The Berlin research group proposed that the exchange of chloride for protons, which are more highly concentrated in the acidic environment of lysosomes than in the rest of the cell, accumulates chloride ions in lysosomes. A high lysosomal chloride concentration may be functionally important.

“In an elegant experimental approach” as Professor Jentsch explains the test of this hypothesis, “Dr. Novarino and Dr. Weinert converted the ClC-5 and ClC-7 chloride-proton exchangers in the mouse into pure chloride conductors (channels). They exchanged a single amino acid out of a total of around 800 present in the ion transporters”. These mutated transport proteins are optimally suited to compensate the charge transfer by the proton pump and therefore should, according to the hypothesis of the research group, support the acidification of the organelles very well.

On the other hand, the uncoupling of chloride transport from proton transport should significantly lower the accumulation of chloride into these organelles. Indeed, this prediction was confirmed experimentally in their mouse model. “Surprisingly,” Professor Jentsch said, “the corresponding mice showed almost the same disease symptoms as with a total lack of the respective proteins.”

With this experiment, the MDC and FMP researchers were able to show for the first time that not only the lack of endosomal/lysosomal acidification, but also a reduced accumulation of chloride ions in these organelles plays a crucial role in generating the severe symptoms of these hereditary diseases, that is a form of kidney stone disease as well as neurodegeneration. A dysregulation of organellar chloride concentration may also play a role in other human diseases.

*Science 11 June 2010, Vol. 328. no. 5984, pp. 1398-1401; DOI: 10.1126/science.1188070; originally published in Science Express on 29 April 2010
*Endosomal Chloride-Proton Exchange Rather Than Chloride Conductance is Crucial for Renal Endocytosis
Gaia Novarino1, Stefanie Weinert1, Gesa Rickheit1,2 & Thomas J. Jentsch1
1 Leibniz-Institut für Molekulare Pharmakologie (FMP)and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany

2 Present address: TaconicArtemis GmbH, Köln, Germany

Science 11 June 2010, Vol. 328. no. 5984, pp. 1401-1403, DOI: 10.1126/science.1188072; originally published in Science Express on 29 April 2010; * Lysosomal Pathology and Osteopetrosis Upon Loss of H+-Driven Lysosomal Cl- Accumulation
Stefanie Weinert1,2, Sabrina Jabs1,2,6, Chayarop Supanchart3, Michaela Schweizer4, Niclas Gimber1,2, Martin Richter1,6, Jörg Rademann1,6,7, Tobias Stauber1,2,Uwe Kornak3,5 & Thomas J. Jentsch1,2
1 Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany
2 Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany
3 Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Germany
4 Zentrum für Molekulare Neurobiologie (ZMNH), Universität Hamburg, Hamburg, Germany
5 Max-Planck-Institut für Molekulare Genetik, Berlin, Germany
6 Freie Universität, Berlin, Germany
7Present address: Institut für Pharmazie, Universität Leipzig, Leipzig, Germany
Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de

Barbara Bachtler | Max-Delbrück-Centrum
Further information:
http://www.mdc-berlin.de/

More articles from Life Sciences:

nachricht Cloud Formation: How Feldspar Acts as Ice Nucleus
09.12.2016 | Karlsruher Institut für Technologie

nachricht Closing the carbon loop
08.12.2016 | University of Pittsburgh

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Closing the carbon loop

08.12.2016 | Life Sciences

Applicability of dynamic facilitation theory to binary hard disk systems

08.12.2016 | Physics and Astronomy

Scientists track chemical and structural evolution of catalytic nanoparticles in 3-D

08.12.2016 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>