Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
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

Join For Free

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 3,000+ scientific posters on ePosters
  • More Than 4,400+ 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

Doubling Down on Dengue
HMS researchers have discovered two ways a compound blocks dengue virus.
Tuesday, April 26, 2016
Fighting Early Stage Alzheimer's
Mouse study suggests possibility of curbing early synapse loss in Alzheimer’s.
Monday, April 04, 2016
Breaking the Chain
Compound prevents multidrug-resistant fungi from pumping out drugs.
Tuesday, February 23, 2016
Breaking Point
Hotspots for DNA breaks cluster in specific genes in developing neurons.
Wednesday, February 17, 2016
The Spice of Life
Scientists discover important genetic source of human diversity.
Tuesday, February 09, 2016
Cytoskeleton Crew
Findings confirm sugar's role in helping cancers survive by changing cellular architecture.
Tuesday, February 09, 2016
The Power of Three
Overlooked portion of cell “death receptor” critical in some cancers, autoimmune diseases.
Tuesday, February 09, 2016
‘Lifespan Machine’ Probes Cause of Aging
Findings suggest that aging has no single mechanism.
Wednesday, February 03, 2016
Photo Finish
Nanoparticles pair photodynamic and molecular therapies against pancreatic cancer in mice.
Tuesday, January 26, 2016
High-fidelity CRISPR
Improved gene-editing tool has no detectable off-target mutations.
Thursday, January 07, 2016
Stem Cell Memory
Scientists find molecular key that prevents the conversion of adult cells into iPS cells.
Tuesday, January 05, 2016
Hit Parade
Researchers are generating a list of compounds that may lead to a trio of new therapeutics.
Tuesday, December 22, 2015
Stockpiling Proteins
New web-based tool allows researchers to measure protein dynamics in embryogenesis.
Wednesday, December 09, 2015
A Natural History of Neurons
Diverse mutations reveal lineage of brain cells.
Monday, October 05, 2015
The Final Word on STAP
Researchers fail to replicate STAP study; computational analysis reveals genomic inconsistency.
Monday, September 28, 2015
Scientific News
Computational Model Finds New Protein-Protein Interactions
Researchers at University of Pittsburgh have discovered 500 new protein-protein interactions (PPIs) associated with genes linked to schizophrenia.
Experimental Drug Cancels Effect from Key Intellectual Disability Gene
A University of Wisconsin—Madison researcher who studies the most common genetic intellectual disability has used an experimental drug to reverse — in mice — damage from the mutation that causes the syndrome.
MicroRNA Pathway Could Lead to New Avenues for Leukemia Treatment
Cancer researchers at the University of Cincinnati have found a particular signaling route in microRNA (miR-22) that could lead to targets for acute myeloid leukemia, the most common type of fast-growing cancer of the blood and bone marrow.
Bioreactors Ready for the Big Time
Bioreactors are passive filtration systems that can reduce nitrate losses from farm fields.
Analysis of Dog Genome will Provide Insight into Human Disease
An important model in studying human disease, the non-coding RNA of the canine genome is an essential starting point for evolutionary and biomedical studies – according to a new study led by The Genome Analysis Centre (TGAC).
‘Mini-Brains’ to Study Zika
Novel tool expected to speed research on brain and drug development.
Finding Factors That Protect Against Flu
A clinical trial examining the body’s response to seasonal flu suggests new approaches for evaluating the effectiveness of seasonal flu vaccines.
New Insights into Gene Regulation
Researchers have solved the three-dimensional structure of a gene repression complex that is known to play a role in cancer.
Controlling RNA in Living Cells
Modular, programmable proteins can be used to track or manipulate gene expression.
Common Class of Cancer Drugs May Not Lead to Cognitive Decline
UCLA study refutes 2015 research suggesting anthracyclines could cause memory loss, other impairments.
Scroll Up
Scroll Down
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
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,400+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!