Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New chemical tool kit manipulates mitochondria, reveals insights into drug toxicity

26.02.2008
Why do nearly 1 million people taking cholesterol-lowering statins often experience muscle cramps? Why is it that in the rare case when a diabetic takes medication for intestinal worms, his glucose levels improve? Is there any scientific basis for the purported health effects of green tea?

A new chemical toolkit provides the first clinical explanation for these and other physiological mysteries. The answers, it turns out, all boil down to mitochondria, those tiny organelles floating around in cellular cytoplasm, often described as the cell’s battery packs.

A research team led by Harvard Medical School assistant professor and Broad Institute associate member Vamsi Mootha has developed a toolkit that isolates five primary aspects of mitochondrial function and analyzes how individual drugs affect each of these areas. These results are published online February 24 in Nature Biotechnology.

Over the last few decades, mitochondria have increasingly been understood as a key determinant of cellular health. On the other hand, mitochondrial dysfunction can lead to many neurodegenerative conditions as well as metabolic diseases such as diabetes. Since mitochondria are responsible for turning the food we eat into the energy that drives our bodies, these and other connections are logical. Nevertheless, there has not yet been a systematic method for thoroughly interrogating all facets of mitochondrial activity.

“Historically, most studies on mitochondria were done by isolating them from their normal environment,” says Mootha, who is also a member of the Center for Human Genetic Research at Massachusetts General Hospital. “We wanted to analyze mitochondria in the context of intact cells, which would then give us a picture of how mitochondria relate to their natural surroundings. To do this we created a screening compendium that could then be mined with computation.”

In order to thoroughly analyze these organelles, Mootha and his team zeroed in on five basic features of mitochondria activity, looking at how a library of 2,500 chemical compounds affected mitochondrial toxic byproducts (like all “chemical factories” mitochondria produce their own toxic waste), energy levels, speed with which substances pass through these organelles, membrane voltage, and expression of key mitochondrial and nuclear genes. (Mitochondria contain their own genome, consisting of approximately 37 genes in humans.)

“It’s just like taking your car in for an engine diagnostic,” explains Mootha. “The mechanic will probe the battery, the exhaust system, the fan belt, etc., and as a result will then produce a read-out for the entire system. That’s analogous to what we’ve done.”

As a result of these investigations, Mootha and his group produced three major findings.

First, the team discovered a pathway by which the mitochondria and the cell’s nuclear genome communicate with each other. They found this by discovering that certain drugs actually broke communication between these two genomes. By reverse engineering the drugs’ toxic effects, they may be able to reconstruct normal function.

Second, the team looked at a class of the cholesterol-lowering drugs called statins. Roughly 100 million Americans take statins, and among that group, about 1 million experience muscle cramping and aches. Previous studies suggested that mitochondria were involved, but clinical evidence remained conflicting. Mootha and his colleagues found that three out of the six statins (Fluvastatin, Lovastatin, and Simvastatin) interfered with mitochondria energy levels, as did the blood-pressure drug Propranolol. When combined, the effect was worse.

“It’s likely that a fair number of patients with heart disease are on one of these three statins as well as Propranolol,” says Mootha, “Our cellular studies predict that these patients might be at a higher risk for developing the muscle cramps. Obviously, this is only a hypothesis, but now this is easily testable.”

The third and arguably most clinically relevant finding builds on a paper Mootha coauthored in 2003, a paper that demonstrated how type 2 diabetes was linked to a decrease in the expression of mitochondrial genes. A subsequent and unrelated paper showed a relationship between type 2 diabetes and an increase in mitochondrial toxic byproducts. Mootha’s group decided to query their toolkit and see if there were any drugs that affected both of these functions, drugs that could boost gene expression while reducing mitochondrial waste.

Indeed, they found six compounds that did just that, five of which were known to perturb the cell’s cytoskeleton, that is, the scaffolding that gives a cell its structure.

“Our data shows that when we disrupt the cytoskeleton of the cell, that sends a message to boost the mitochondria, turning on gene expression and dropping the toxic byproducts,” says Mootha. “The connection between the cytoskeleton and mitochondrial gene expression has never been shown before and could be very important to basic cell biology.”

Of the five drugs that did this, one, called Deoxysappanone, is found in green tea and is known to have anti-diabetic effects. Another, called Mebendazole, is used for treating intestinal worm infections. This connection gives a rationale to case reports in which diabetics treated with Mebendazole have described improvements in their glucose levels while on the drug.

The researchers intend to further investigate some of the basic biological questions that this study has raised, foremost being the relationship between the cytoskeleton and mitochondria. They also plan on using this toolkit to develop strategies for restoring normal mitochondrial function in certain metabolic and neurodegenerative conditions where it has broken down.

David Cameron | EurekAlert!
Further information:
http://www.hms.harvard.edu

Further reports about: Mootha TEA Toolkit cytoskeleton effect mitochondria mitochondrial statins toxic

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>