The last time I read about rotenone was back when I was a grad student in fisheries biology. That’s why, when Ian Blair, PhD, director of the Center for Cancer Pharmacology, sent me his latest paper, from the Journal of Biological Chemistry on the compound, I was intrigued. Rotenone is a naturally occurring chemical in the seeds and stems of several plants, such as jicama, and is a broad pesticide, insecticide, and piscicide, or literally fish killer. Rotenone was used by indigenous tribes in the Americas to catch fish by crushing seeds and adding to corralled water. (The chemical is still used for limited purposes by modern-day fisheries biologists.) Because rotenone messes with cellular respiration, fish rise to the surface to gulp air, where they can be more easily caught.
This happens because rotenone inhibits the electron transport chain deep within the mitochondria, the cell’s proverbial powerhouse. A compound called acetyl-CoA is linked with this transport reaction and is needed to make the energy molecule ATP to run the cell. Rotenone interferes with this basic function.
Rotenone exposure is also associated with Parkinson’s disease (PD) in humans, but the exact mechanism is unknown. In fact, rotenone is used to induce a rodent model of PD. Mitochondrial abnormalities have been well documented in PD patients, often coinciding with elevated markers of oxidative stress. Despite this evidence, not much is known about how nerve cells die because of the stress.
Blair is also the director of the Penn Superfund Research and Training Program Center, within the Center of Excellence in Environmental Toxicology (CEET), so rotenone work is relevant to his interest in environmental toxins. In fact, the CEET training program funds the first author of the paper, Andrew Worth, a doctoral student in the Blair lab.
The team found that rotenone induced increased lipid breakdown and glutamine use by cells and that these metabolic shifts compensated for impaired energy production in response to rotenone. This is important to know because metabolic abnormalities associated with mitochondrial dysfunction may play an important role in the development of some forms of neurodegeneration. Nathaniel Snyder, PhD one of the other co-authors of the paper who recently completed his postdoctoral research in Blair’s lab and accepted a faculty position at the A. J. Drexel Autism Institute at Drexel University, will be using similar approaches to examine mitochondrial dysfunction in models of autism.
Cells basically find alternate ways to make acetyl-CoA if one way is impaired. For example, glutamine is made via the enzyme glutaminase to make glutamate, which can ultimately be converted to acetyl-CoA. This path is critical for sustaining some tumors, so there are also important implications for cancer drugs. The paper showed a third pathway to make the essential acetyl-CoA via up-regulation of fatty acid use and oxidation in response to rotenone.
The published findings have implications for diseases other than PD and cancer. For example, the Blair group is also studying Friedreich’s Ataxia (FA), a rare genetic disorder in which deficiencies in the protein frataxin are thought to lead to mitochondrial dysfunction and subsequent neurological defects. Current efforts are aimed at using isolated platelets from FA patients as a surrogate tissue for identifying previously unknown metabolic abnormalities that may play an important role in the pathogenesis of FA.
Image courtesy of the Illinois Department of Natural Resourses via Flickr