However, recent studies suggest that mitochondria do much more than generate energy. They are intimately involved in cell signaling, raising a red flag during times of cellular stress, such as when viruses invade or oxygen levels drop. It now appears that subtle abnormalities in mitochondria contribute not only to rare metabolic disorders but also to many common diseases, including chronic hepatitis, cancer, and certain aging-related diseases, such as type 2 diabetes. Says Gerald I. Shulman, an HHMI investigator at Yale University School of Medicine whose area of expertise is diabetes, "We're moving into areas that affect large numbers of people—the 7 percent of the population with diabetes—and that gets a lot of attention."

These days, mitochondria often take scientists by surprise. "Researchers keep stumbling into mitochondria,” says Gerald S. Shadel, a molecular biologist at Yale University School of Medicine who studies mitochondria and disease. “That probably reflects the fact that mitochondria are involved in many things besides what was historically assigned to them; people in many fields are now making important connections."

Research on mitochondria heated up in the 1990s, when studies revealed that they play a key role in signaling programmed cell death. In 1996, Xiaodong Wang, an HHMI investigator at the University of Texas Southwestern Medical Center at Dallas, made the surprising discovery that mitochondria release a molecule called cytochrome c, triggering a signaling cascade that leads to cell suicide, usually during embryonic development or in response to cellular stress or damage. Then, in 2001, the late HHMI investigator Stanley J. Korsmeyer reported that the activation of a pore in the mitochondrial membrane launches this process by enabling the cytochrome c signal to flow into the rest of the cell.

Now, another protein in the mitochondrial membrane has been discovered that for the first time links this organelle to the immune system. Zhijian "James" Chen, an HHMI investigator also at the University of Texas Southwestern Medical Center, found a protein in the mitochondrial membrane that contributes to viral defense. Chen wanted to know how cells detect and mount a response to infection by a virus—in particular, what activates the cell to produce important antiviral molecules called interferons (which are also used as medical therapies). His team searched for signaling proteins involved in antiviral immune responses and found a protein that appeared to activate two transcription factors known to trigger interferon production. They then engineered cells that express large amounts of this protein and grew them in culture with viruses. Monitoring to see what would happen, they found that the cells had gained antiviral immunity. Conversely, when they silenced the protein's expression, the resulting cells were swamped with replicating viruses.

The big surprise came when the group broke open the cells, spun them in a centrifuge, and found this protein not in the liquid extract but in the fatty membrane fraction. Using confocal microscopy, they pinpointed its location in the mitochondrial membrane and so decided to name it Mitochondrial Antiviral Signaling Protein, or MAVS. "It was quite surprising, but also very exciting," says Chen, because this was the first time anyone had found a protein involved in immunity that was part of the mitochondrion. In fact, several other groups had encountered the same protein but didn't figure out its cellular location, which, Chen's team found, is essential for the signaling function of MAVS.

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