The mitochondrion is called the powerhouse of the cell because it creates the energy required for life's activities, such as breathing, eating, and reproducing. The mitochondrion also plays a role in helping cells die, also a natural part of life. Now, Columbia University Health Sciences investigators have found another function for this subcellular organelle: The mitochondrion appears to help fight foreign invaders in a process that could help the lungs fight infection while simultaneously taking in oxygen.

Dr. Jahar Bhattacharya, professor of clinical physiological medicine at Columbia's College of Physicians & Surgeons at St. Luke's-Roosevelt Hospital Center, Dr. Kaushik Parthasarathi, associate research scientist, and their colleagues found, for the first time, that the mitochondrion releases chemicals in rat lung capillaries—a major site of inflammation in the organ—in a key initiation step of the immune response.

Using microscopes and real-time digital imaging to study living capillaries in lungs surgically removed from rats, they have shown that mitochondria inside endothelial cells (cells that line the blood vessels) near the site of an infection release a chemical that is transformed into hydrogen peroxide, which then triggers an immune response.

Hydrogen peroxide acts inside the cell to push a substance, called P-selectin, to the cell surface, making the cell sticky and attractive to immune cells called leukocytes floating in the blood. After binding the endothelial cells, the leukocytes then can find their way to the site of local infection where they attack the pathogen and cause inflammation. The research was published in the December 2002 Journal of Immunology.

By studying live capillaries in an intact lung, the researchers could observe endothelial cells in a more natural environment than cells cultured in a petri dish—the standard approach for endothelial cell research. The new method helped the researchers identify two types of endothelial cells that play different roles in the inflammatory process: one with many mitochondria found at capillary branch points; and another with few mitochondria located away from the branch points, and called mid-segment capillary sections.

The technique also allowed them to tease out the steps in the inflammatory cascade. One of the keys to the inflammation response is calcium's role as a signaling agent, Dr. Bhattacharya says. It was known that the cell's calcium has to increase to start the signaling chain to move P-selectin but the sequential steps were unknown.

To determine the sequence of inflammatory signaling, the researchers raised the cell calcium levels by infusing lung venular capillaries—one of three types of capillaries involved in gas exchange in the lung—with tumor necrosis factor-a (TNF-), a well-known signaling chemical that binds to a cell receptor.

The researchers found that TNF- affected only the branch point endothelial cells, causing a local inflammation response there. TNF- caused an internal release of calcium from endosomes into the cytoplasm and an influx of calcium from outside the cell. The release of endosomal calcium occurred close to the mitochondria, which then released what became hydrogen peroxide and the P-selectin inflammation cascade began.

Dr. Bhattacharya and his colleagues conclude that the mid-segment capillary sections do not have much of a role in the inflammation response to TNF-. The mid-segment endothelial cells are mitochondria-poor, he says, possibly because the lung needs to localize the defense response to capillary branch points, keeping the middle parts of the capillaries open for the purpose of oxygen uptake from the adjoining air sacs.

Since the research was conducted in venular capillaries, Dr. Bhattacharya now would like to determine if the mitochondrial role in inflammation happens in a similar way in the other two capillary networks—the arteriolar and septal capillaries. The mitochondrial contents of endothelial cells in these other vessels are not known. He also wants to reproduce the research in a whole animal model and study whether mitochondria continue participating in the inflammation for some time.

For now, the relevance of the findings remains unknown, but Dr. Bhattacharya hopes the research will inspire investigators who study mitochondria and inflammation in neural degeneration, myopathy, sepsis, and lung diseases such as pulmonary edema.

"Since the understanding of mitochondria-induced pathology is in its infancy, it is too early to predict whether mitochondrial inhibition would be beneficial," Dr. Bhattacharya says. "However, our research indicates the importance of considering inhibition of mitochondrial hydrogen peroxide as a potential therapeutic strategy."

The research was supported by several grants from the National Institutes of Health.