Jean Schaffer, Washington University in St. Louis

Lots of lipids. When large amounts of fat are present in the cell, snoRNAs (red) move outside of the nucleus (green) and into the cytoplasm of the cell, where they trigger cell death.

(Cellular) Death by Chocolate

Those extra slices of chocolate cake may do more than just add a few extra pounds—they can create a toxic environment that kills your cells. Now researchers say they have identified an important player in this process: a type of RNA previously thought only to modify other RNA molecules. Blocking these surprising villains could provide a new way to combat fat toxicity, a leading cause of heart and kidney failure.

Most of the time when we overindulge, adipose tissue, which is made up of the body's professional fat-storing cells, mops up any excess calories circulating in the bloodstream. Adipose cells, however, can't always cope with the large amounts of fat in modern diets, and the excess fat circulates in the bloodstream. When other cells in the body take in the extra fat, it can disrupt their internal mechanics and gene activity, causing them to commit suicide. On a large scale, this cellular kamikaze can lead to kidney and heart failure.

Today in Cell Metabolism, researchers led by Jean Schaffer, a cardiologist at Washington University in St. Louis, report that they identified a single gene that seems to be responsible for this toxicity-induced cellular death. Sections of the gene, known as rpL13a, do not code for a protein, the researchers found, but rather for a type of RNA molecule known as a small nucleolar RNA (snoRNA). The main job of these molecules is to modify other RNA molecules.

To figure out if these snoRNAs trigger cell death in a high-fat environment, Schaffer and colleagues added the three snoRNAs coded for by the gene to cells with a disrupted rpL13a gene. The cells committed suicide. Other experiments showed that large amounts of fatty acids increased the production of the protein and snoRNAs encoded by rpL13a, and that blocking the action of the snoRNAs produced by rpL13a decreased cell death in response to a variety of stresses, not just excess fat. The researchers added a fluorescent label to the snoRNAs and found that, rather than staying in the nucleus as previously thought, they were located in the cytoplasm. Finding snoRNAs in a new location may mean that these molecules have a range of functions that researchers have never even thought to look for.

This study opens up new ways to prevent physiological damage from diseases such as diabetes and obesity, Schaffer says, because now researchers know what molecules to target for future drug development. The study is also significant, says biologist E. Stuart Maxwell of North Carolina State University in Raleigh, because it reveals that snoRNAs help determine whether cells commit suicide. "It's going to make people start to think about the roles that these RNAs play" outside of their traditional functions, which were traditionally thought to be limited to modifying other RNA molecules, he says.

Posted in Biology