When cells "eat" their own powerhouses: Scientists have solved the mystery surrounding a basic cellular process

Date: September 30, 2013

Posted in:  http://www.sciencedaily.com/releases/2013/09/130930140518.htm

(Artist's rendering of mitochondrion interior. (Credit: © Mopic / Fotolia

A combination of unexpected experimental results and hard laboratory work allowed a multidisciplinary research group from the University of Pittsburgh to report in the October 1 issue of NATURE CELL BIOLOGY that they were able to uncover the mystery surrounding a cellular process essential to cell health.

With the discovery of a mechanism used by the mitochondria - tiny organelles inside the cell sometimes referred to as "power plants" - to signal that they are damaged and need to be eliminated, the research team opened the door to research possibilities for curing diseases such as Parkinson's disease, which is assumed to be caused by a dysfunction of the mitochondria in nerve cells.

"This is a process of hi in order to get rid of offices, cells are activated to get rid of damaged mitochondria and preserve normal mitochondria, if this process is successful then the normal mitochondria multiply and the cell lives" says Dr. Valerian Kagan, senior author of the article, professor and vice chair of the School of Public Health, Department of Occupational Health and environmental studies at the University of Pittsburgh. "This is a beautiful and efficient mechanism that we will try to test in disease models."

Dr. Kagan, a Fulbright scholar currently serving as Visiting Chair for Science and Environmental Research at McMaster University in Ontario, Canada, compares the process to cooking a Thanksgiving turkey. "You put the turkey in the oven and the outside browns, but you can't determine if it's ready just by looking at it. So you put a thermometer in it and when the temperature jumps up you decide it's ready and you can eat it," he says. "Mitochondria give a similar "eat me" signal after they have finished functioning properly"

Cardiolipins, so named because they were found in heart tissue, are a component of the inner membrane of the mitochondria. When a mitochondrion is damaged, the cardiolipins move to the outer membrane of the mitochondrion where they send a message to the cell to destroy the mitochondrion. But this is only part of the process, says Dr. Charlin T. Chu, professor in the Julio Martinez Chair in Neuropathology at Pitt School of Medicine in the Department of Pathology and senior author of the article. "It's not just that the turkey timer went off, the question is who holds the hot meat and brings it to the table." It turns out that it is a protein called LC3. One part of it binds to cardiolipin and then forms a special structure that surrounds the damaged mitochondrion that carries it to the digestion centers in the cell. The research began about a decade ago after a conversation between Dr. Kagan and Dr. Cho who studied self-eating in Parkinson's patients and looked for a mitochondrial change on its surface that could signal the LC3 protein to recycle the damaged organelles. It turned out they were working on different sides of the same puzzle.

Together with Dr. Hulia Bair, director of pediatric intensive care research at Children's Hospital in Pittsburgh at UPMC and a professor at the University of Pittsburgh Department of Intensive Care and a team of 24 researchers, the 3 senior researchers worked on how to put all the pieces of information together to explain the issue of mitochondrial signaling.

Now that they have found the basic mechanism, Dr. Cho points out, many research directions will open up.

"Many questions remain open," she says. "What is the process that keeps cardiolipin from moving out of the mitochondria? How does this pathway integrate with the other pathways that affect the onset of Parkinson's disease? It is interesting that two genes associated with familial Parkinson's disease are also involved in the elimination of mitochondria."

Dr. Bair explains that while such a process can occur in any cell with mitochondria, its operation in nerve cells is especially important. Because these cells do not reproduce or divide, nor are they created like other cells in the body. "I think this has consequences for brain-damaged patients," she says. "The mitochondrial "eat me" signaling to me can be used as a target site for treatment in the following sense, some of the damaged mitochondria need to be removed, but on the other hand we don't want an uncontrolled process

There needs to be a level of balance that we seek to achieve with the help of medication if the body is unable to do it on its own."

bibliography

Charleen T. Chu, Jing Ji, Ruben K. Dagda, Jian Fei Jiang, Yulia Y. Tyurina, Alexandr A. Kapralov, Vladimir A. Tyurin, Naveena Yanamala, Indira H. Shrivastava, Dariush Mohammadyani, Kent Zhi Qiang Wang, Jianhui Zhu , Judith Klein-Seetharaman, Krishnakumar Balasubramanian, Andrew A. Amoscato, Grigory Borisenko, Zhentai Huang, Aaron M. Gusdon, Amin Cheikhi, Erin K. Steer, Ruth Wang, Catherine Baty, Simon Watkins, Ivet Bahar, Hülya Bayır, Valerian E. Kagan. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nature Cell Biology, 2013; DOI: