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

BOSTON, Mass. (Feb. 24, 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.)