Corporate Banner
Satellite Banner
Genotyping & Gene Expression
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

New Chemical Toolkit Manipulates Mitochondria, Reveals Insights into Drug Toxicity

Published: Tuesday, February 26, 2008
Last Updated: Wednesday, February 27, 2008
Bookmark and Share
A research team led by a Harvard Medical School assistant professor has developed a toolkit that isolates five primary aspects of mitochondrial function.

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.

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.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Facebook for the Proteome
Researchers have developed a network for describing protein-protein interactions that can then be used to examine protein interactions that may have biological or clinical significance.
Friday, July 17, 2015
New Techniques Reveal “Extreme” Gene Copy Range
New findings give scientists the first precise way to study places in the genome where the number of copies of a sequence varies widely from person to person.
Monday, February 02, 2015
Variation in Three Genes Influences Risk of Age-Related Macular Degeneration
Researchers discover a common, noncoding variant in the CFH gene that is associated with AMD.
Thursday, September 07, 2006
Scientific News
Oxitec ‘Self-Limiting Gene’ Offers Hope for Controlling Invasive Moth
A new pesticide-free and environmentally-friendly way to control insect pests has moved ahead with the publication of results showing that Oxitec diamondback moths (DBM) with a ‘self-limiting gene’ can dramatically reduce populations of DBM.
Teeth Reveal Lifetime Exposures to Metals, Toxins
Researchers have identified dental biomarkers to reveal links between early iron exposure and late life brain diseases.
Scientists Identify Schizophrenia’s “Rosetta Stone” Gene
Scientists have identified a critical function of what they believe to be schizophrenia’s “Rosetta Stone” gene that could hold the key to decoding the function of all genes involved in the disease.
Could a simple saliva test detect Alzheimer's?
Researchers have presented findings suggesting that a simple, non-invasive diagnostic for Alzheimer's could be within reach.
New Research Advances Genetic Studies in Wildlife Conservation
‘Next-gen’ DNA sequencing of non-invasively collected hair expands field of conservation genetics.
AncestryDNA and Calico to Research the Genetics of Human Lifespan
Collaboration will analyze family history and genetics to facilitate development of cutting-edge therapeutics.
Gene Variation Identified for Teen Binge-Eating
Researchers have identified a gene variant which can lead to teenage binge eating, they hope that their work will inform the development of future preventative measures.
Adaptimmune's Novel Cancer Therapeutics Show Positive Clinical Trial Results
The company has announced that positive data from its Phase I/II study of its affinity enhanced T-cell receptor (TCR) therapeutic targeting the NY-ESO-1 cancer antigen in patients with multiple myeloma has been published.
Gene Testing Now Allows Precision Medicine for Thoracic Aneurysms
Researchers at the Aortic Institute at Yale have tested the genomes of more than 100 patients with thoracic aortic aneurysms, a potentially lethal condition, and provided genetically personalized care.
Facebook for the Proteome
Researchers have developed a network for describing protein-protein interactions that can then be used to examine protein interactions that may have biological or clinical significance.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!