Cell suicide is a widespread phenomenon. When a cell is worn out, used up or irreparably damaged, or if changes in its DNA threaten to turn the cell cancerous, a special cellular mechanism is called upon to end things before trouble can ensue. But living cells have no access to ropes, knives or sleeping pills; they must resort to what’s at hand. A common method of cell suicide _ a process scientists refer to as apoptosis _ involves opening up the membranes of vital organelles called mitochondria and letting the proteins inside escape into the body of the cell. These normally harmless proteins team up with other proteins in the cell to disrupt its normal life processes and eventually destroy it.
Prof. Atan Gross
of the Institute’s Biological Regulation Department investigates some of the steps in this complex process, specifically the proteins that deliver the suicide message to the mitochondria and initiate the necessary chain of events there. Many years ago, Gross started studying a protein called BID that’s involved in the pathway to suicide. Further research showed that this molecule must first undergo cleavage by another molecule before it can proceed with the suicide plan, and that the shortened version, called truncated BID (or tBID), activates another two proteins called BAX and BAK further down the line. The result of all this activity: The mitochondria develop a leaky outer membrane, which not only interferes with their main function – turning nutrients into the energy that powers the cell – but releases several different proteins into the body of the cell. Some of these proteins are among those directly implicated in the advanced stages of apoptosis, and several of the others may be involved as well.
A few years ago, Gross and his research team identified yet another player in this drama – a novel, previously uncharacterized protein sitting on the outer membrane of the mitochondria called mitochondrial carrier homolog 2 (or MTCH2).
What does this protein do? To find out, Gross and his team, including Dr. Yehudit Zaltsman-Amir and research student Liat Shachnai, began by creating mice embryos that lacked the gene for MTCH2. But these mice never made it to birth, a sign that the protein plays an important role in the body. Next, they created mice in which the gene could be neutralized (“knocked out”) in a specific organ at a specific time. The scientists then chose to knock out the gene in the liver.
Their results, which appeared in Nature Cell Biology, showed that MTCH2 acts as a receptor. From its post on the outside of the organelle, it attaches to a passing tBID molecule and transfers a signal to the inside of the mitochondrial membrane. The experiments showed that when this receptor was absent, the process stalled at some point after BID underwent cleavage. Most of the tBID failed to make it to the mitochondria, the suicide message was not passed on to BAX or BAK, and the membranes remained leak-free.
Gross and his team are continuing to investigate MTCH2, looking for other functions it may have. “For many proteins, apoptosis is the ‘night job.’ The ‘day job’ can be something completely different,” he says. “We think that MTCH2 may not even be a receptor in its day job; it is very similar to the mitochondrial carriers that transport various substrates across the mitochondrial membranes. We’re now working on finding out what it does when it’s not promoting cell suicide, and our preliminary studies hint at an intriguing connection to fat metabolism.”
Because apoptosis is vital to everything from embryonic development to everyday cell and tissue replacement to cancer prevention, the MTCH2 protein presents a promising target for drugs. Gross: “In cancer, cells fail to commit suicide; other diseases stem from too much or inappropriate apoptosis. We think we can find ways to manipulate the interaction between tBID and MTCH2 to address these problems.” Yeda, the technology transfer arm of the Weizmann Institute, has applied for patents on the protein, and research is already under way in Gross’s lab and collaborating groups to map out the physical interaction domains between the two proteins and develop new molecules that can block or enhance this interaction in disease processes.
Prof. Atan Gross's research is supported by the Dr. Josef Cohn Minerva Center for Biomembrane Research; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Victor Pastor Fund for Cellular Disease Research; and the Pearl Welinsky Merlo Foundation.