Initial investigation found communication pathway between organelle and cell’s nuclear genome, insights on statin side effects, and connection between cytoskeleton and mitochondrial gene expression.

Researchers have developed a chemical toolkit to manipulate mitochondria in its normal cellular environment. After introducing nearly 2,500 compounds to this platform many of which are FDA-approved the researchers say that they were able to discern new insights into basic mitochondrial function, which in turn revealed why some commonly used drugs have particular adverse effects.

“Historically, most studies on mitochondria were done by isolating them from their normal environment,” says Harvard Medical School assistant professor and Broad Institute associate member Vamsi Mootha. “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.”

The toolkit isolates five primary aspects of mitochondrial function: toxic byproducts, energy levels, speed with which substances pass through these organelles, membrane voltage, and expression of key mitochondrial and nuclear genes.

The team produced three major findings. First, the team found a pathway by which the mitochondria and the cell’s nuclear genome communicate with each other. They discovered this through the identification that certain drugs actually broke this connection. By reverse engineering the drugs’ toxic effects, they may be able to reconstruct normal function.

Second, the team looked at statins to analyze previous suppositions that mitochondria were involved in side effects such as muscle cramping and aches. They 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.”

Finally, they found a connection between the cell’s cytoskeleton and mitochondrial gene expression. A 2003 paper that Mootha coauthored 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 could boost gene expression while reducing mitochondrial waste.

They found six compounds that did just that, five of which were known to perturb the cell’s cytoskeleton. “Our data shows that when we disrupt the cytoskeleton of the cell, that sends a message to boost the mitochondria, it turns on gene expression and drops the toxic byproducts,” explains Mootha.

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

Mootha’s team included scientists from the Broad Institute, the Center for Human Genetic Research at the Massachusetts General Hospital, Dana-Farber Cancer Institute, and Department of Systems Biology at Harvard Medical School. The results were published online February 24 in Nature Biotechnology.

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