Scientists at the Texas A&M Health Science Center Institute of Biosciences and Technology (IBT) in Houston have solved one of the great mysteries of cell biology: the regulation of peroxisomes. Their recent article, published in Nature Cell Biology, is the third and last of a series of papers and represents a culmination of almost a decade of research.

All cells have peroxisomes, which are the organelle that breaks down fatty acids. In the process, they also generate large amounts of reactive oxygen species (ROS). These ROS cause cellular damage, a primary cause of aging and degenerative diseases, and can damage DNA, one of the causes of cancer. The cell has to find the right balance between having enough peroxisomes to do the job of breaking down fats and not having so many that levels of ROS rise out of control, damage the cell and cause disease.

“We have never really understood how the cell knows when it has the right number of peroxisomes,” said Cheryl Lyn Walker, Ph.D., director of the Texas A&M IBT and the senior author on the paper. “That has been one of the great mysteries in the cell biology world, one to which we may just have found the solution. What we discovered is that key proteins that function in the cell as tumor suppressors are actually responding to ROS and eliminating excess peroxisomes, which helps protect cells in the body from becoming cancerous.”

These two tumor suppressors are ataxia telangiectasia mutated (ATM) and the tuberous sclerosis complex (TSC2). In previous work, Walker and her team discovered that ROS activate ATM, which signals TSC2, which then helps regulate the number peroxisomes in the cell.

“That was a complete surprise,” Walker said, and resulted in Walker and her group receiving the Cozzarelli Prize in Biological Sciences from the National Academy of Sciences in 2010. “However, that was just the beginning, and we still had a lot to learn about what this signaling pathway was doing in the cell.”

The current work brings these pieces together to show that both ATM and TSC2 are resident on the peroxisome itself. They can sense the ROS being made and send signals to the cell to remove an overactive peroxisome though the process of autophagy—or “self-eating”—to destroy the problematic peroxisome.

“The idea of focusing on peroxisomes as a cause of cancer, and perhaps a target for prevention and therapy, is a new insight,” Walker said. “Once we can link dysregulated peroxisome biology to specific cancers, there may be new therapeutic intervention that can be built using drugs already in clinical trials to regulate the number of peroxisomes, perhaps by controlling the process of autophagy itself.”

Walker is also quick to point out that this study was a collaborative effort between researchers at several institutions across the country, including Tanya Paull from the University of Texas at Austin; Michael B. Kastan, director of the Cancer Center at Duke University, who has spent his career working on ATM; and Tej Pandita at Methodist Hospital in Houston, who is an expert on DNA repair. “But in the end,” Walker said, “it was really the talented trainees in the lab, Drs. Jiangwei Zhang and Durga Nand Tripathi and graduate student Ji Jing, who made these breakthroughs and who are already hard at work on the next ‘installment’ in the story. Stay tuned.”

— Christina Sumners

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