BioWorld International Correspondent

LONDON - Mitochondria from yeast can break proteins down into peptides and export these to the cytosol, researchers have shown. The finding adds to a previous study that showed that mammalian cells can present peptides from mitochondria on their surface in conjunction with Class I major histocompatibility complex molecules.

Lesley Young, who took part in the research while a Medical Research Council research fellow at the Division of Immunology of the Department of Pathology at the University of Cambridge, UK, told BioWorld International: "We do not know what the function of this process is, but we can speculate that a process that is apparently conserved from yeast to mammals is likely to have an important function, maybe to do with communication between the mitochondria and the rest of the cell."

The study in yeast, by collaborative researchers in the UK and Germany, is published in Science, in a paper titled "Role of the ABC Transporter Mdl1 in Peptide Export from Mitochondria." The paper also demonstrates that a protein located on the inner membrane of the mitochondria plays a key role in exporting peptides.

Young predicted that there would be little immediate commercial interest in the finding, which opens up a completely novel area of basic research. She said, however, that a better understanding of the biology of mitochondria would be of interest to groups working on apoptosis (programmed cell death), or on the many diseases caused by mitochondrial defects.

For her Ph.D. thesis, she had shown that a peptide derived from the mitochondria went on to be presented by Class I MHC molecules on the surface of the cell. This, and experiments by the group of Kirsten Fischer Lindahl in the U.S., suggested to me that mitochondria could release peptides - and nobody had ever described anything like that before," she said. "While there was a lot of information about protein import into mitochondria, there was nothing known about how anything as large as a peptide would get out from these organelles."

Clearly some kind of protein breakdown was involved, so Young contacted Thomas Langer, then at the Institute for Physiological Chemistry at the University of Munich in Germany, who had published many papers investigating the role of mitochondrial proteases. They decided to collaborate.

Langer had used yeast as a model system, because the cells are easy to grow and the mitochondria easy to isolate. In addition, it is relatively easy to create mutant strains of yeast. For their joint study, Young, Langer and their colleagues used radioactively labeled methionine to track the progress of proteins synthesized by the mitochondria. Young, who is joint first author of the paper with Klaus Leonhard, also of the University of Munich, said: "We looked to see whether these proteins were maintained within the mitochondria or whether peptides derived from them were released. We found that they were indeed released, and started to look at how that happened."

Young's work had shown that a molecule belonging to the family known as ABC transporters was involved in exporting the peptide that she had studied from the cytosol to the endoplasmic reticulum of rat cells. The study reported in Science addressed how, in yeast, the peptide could get into the cytosol in the first place.

So the collaborators searched a yeast DNA database for genes that looked similar to those which encode ABC transporters. They identified one that - unlike many - was not known to be associated with a particular cellular location. They then went on to make mutants that lacked the gene for this transporter, and studied what effect this had on the release of the labeled peptides.

Young said: "It turned out that knocking out the gene for this protein, which is called mdl1, significantly reduced the release of the peptides. But it did not completely inhibit the release of all peptides."

Langer knew from his work on mitochondrial proteases that these molecules could drag a protein from one side of a membrane to the other during the process of protein degradation. The group therefore decided to cross mutant yeast that lacked the gene for a protease that is found inside mitochondria, with those that lacked the gene for mdl1.

"We found that this almost completely abrogated the peptide export," Young said. "From these findings, we conclude that there are two ways for mitochondria to release peptides. The first route involves the mdl1 transporter, and the second involves cleavage by a mitochondrial protease."