New chemical toolkit reveals how drugs affect mitochondrial functionFebruary 25th, 2008 - 1:44 pm ICT by admin
London, February 25 (ANI): A team of scientists from Harvard Medical School and Broad Institute has developed a chemical toolkit for manipulating mitochondriatiny organelles floating around in cellular cytoplasm that are often described as the cells battery packsin its normal cellular environment.
Lead researcher Dr. Vamsi Mootha says this toolkit isolates five primary aspects of mitochondrial function, which may reveal why some commonly used drugs have particular side effects.
During the study, the researchers used their toolkit to analyse the effects of about 2,500 chemical compounds, many of which are FDA-approved, on mitochondrial activity.
The research team mainly focussed on the effects of such compounds on five basic features of mitochondria activitynamely mitochondrial toxic byproducts, energy levels, speed with which substances pass through these organelles, membrane voltage, and expression of key mitochondrial and nuclear genes.
The investigations carried out by the researchers produced three major findings, one of which was a pathway by which the mitochondria and the cells nuclear genome communicate with each other.
Mootha said that that discovery resulted from the finding that certain drugs actually broke communication between the two genomes. According to him, by reverse engineering the drugs toxic effects, they might be able to reconstruct normal function.
Secondly, the research team discovered that three of the six cholesterol-lowering drugs called statinsFluvastatin, Lovastatin, and Simvastatininterfered with mitochondria energy levels, as did the blood-pressure drug Propranolol. When the two medications were combined, the effect was worse.
Its likely that a fair number of patients with heart disease are on one of these three statins as well as Propranolol. 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, Nature Biotechnology quoted Mootha as saying.
The third and arguably most clinically relevant finding builds on previous studies that linked type 2 diabetes with a decrease in the expression of mitochondrial genes as well as an increase in mitochondrial toxic byproducts.
With the help of their toolkit, Mootha and his colleagues found six compounds that affected both of these functions i.e. boosting gene expression while reducing mitochondrial waste. Five of such compounds were known to perturb the cells cytoskeleton, 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. The connection between the cytoskeleton and mitochondrial gene expression has never been shown before and could be very important to basic cell biology, Mootha said.
He also revealed that five compounds identified by his team included Deoxysappanone, which is found in green tea and known to have anti-diabetic effects. The compounds also included Mebendazole, which is used for treating intestinal worm infections, he added.
According to him, the 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 say that the relevance of their study lies in the fact that it provides the first comprehensive approach to probing how individual drugs affect all major aspects mitochondrial function.
They are now planning to further investigate the relationship between the cytoskeleton and mitochondria, and to use their toolkit to develop strategies for restoring normal mitochondrial function in certain metabolic and neurodegenerative conditions where it has broken down. (ANI)
Tags: blood pressure drug, cellular environment, cellular studies, chemical compounds, cholesterol lowering drugs, cytoplasm, energy levels, genomes, harvard medical school, lovastatin, membrane voltage, muscle cramps, nuclear genes, organelles, propranolol, reverse engineering, statins, toxic byproducts, toxic effects, vamsi mootha