Aug. 11, 2006 UCLA chemists studying a protein associated with a rare genetic disease may also be gaining insights into cancer and heart disease.
Carla Koehler, a UCLA associate professor of chemistry and biochemistry, and Steven Claypool, a UCLA postdoctoral scholar in chemistry and biochemistry, report in the current issue of the Journal of Cell Biology about the "tafazzin" protein, which plays a key role in Barth syndrome. This rare condition afflicts boys and damages the heart, immune system and mitochondria. If not diagnosed, boys with the disease have only a 30 percent chance of survival to age 4; the cause of death is often cardiac failure. Mutations in the tafazzin gene lead to Barth syndrome, said Koehler, who noted that tafazzin is named after an Italian cartoon character.
Barth syndrome appears to be a disease of the mitochondria, the tiny power generators in cells that burn food and produce most of the cells' energy. Each human cell contains several hundred mitochondria. Mitochondria control cell growth, tell cells when to live and die, and are, Koehler said, the "forgotten part of the cell."
Koehler and Claypool are the first scientists to show where the tafazzin protein normally is located and where it has moved in some patients with Barth syndrome who have a plethora of different disease-causing mutations. Human mitochondria have what can be considered four "rooms": a matrix, an inner membrane, an intermembrane space and an outer membrane. Claypool discovered that the tafazzin protein is in the mitochondria, normally in the inner and outer membranes' lining, facing the intermembrane space in a unique way.
"We have shown that tafazzin associates with both the outer membrane and the inner membrane, always facing the intermembrane space," Claypool said. "Tafazzin protrudes into the intermembrane space from both the outer and inner membranes. To define a protein's function, it is critical to know its location in the cell."
In Barth syndrome patients who carry the mutations Koehler and Claypool have characterized, the protein has moved into the mitochondria's matrix, and thus is not in the right "room" to function properly. The chemists modeled each of the mutations in baker's yeast tafazzin; baker's yeast, which is a single-cell organism whose mitochondria are very similar to those of human cells, allows for sophisticated genetic experiments.
"What we are doing is impossible to study in human mitochondria," said Koehler, a member of UCLA's Jonsson Cancer Center, Molecular Biology Institute and the Brain Research Institute. "We can make these yeast mitochondria easily and knock down particular genes to provide insights into humans."
"Three of the mutations were mislocalized to the mitochondrial matrix; the fourth mutation we characterized localized normally but was assembled inappropriately," Claypool said. "The mislocalization or misassembly of these mutants disturbed the dance of biology and inactivated tafazzin's function."
Three years ago, when Claypool joined Koehler's laboratory after earning his Ph.D. in immunology from Harvard, almost nothing was known about the tafazzin protein.
Koehler and Claypool believe the tafazzin protein may be associated with cardiolipin, the signature lipid of mitochondria, which has been implicated in other diseases, including those of the heart. Lipids are the major constituent of membranes, which form the barriers in cells.
Is damage from heart attacks caused by problems with cardiolipin? The answer is not yet known, Koehler said.
"In cardiac disease, mitochondria often malfunction," Koehler said. "Cardiolipin is an important lipid in this process; if it becomes damaged, the mitochondria become leaky and do not function as well. Tafazzin may be important in repairing lipids, including cardiolipin, but we have not shown that yet. A better understanding of the biology of cardiolipin could present strategies for combating cardiac diseases and cancer."
Cancers are also associated with defects in mitochondria, Koehler said. Within the cell, signaling must occur between the mitochondria and the nucleus. When the signaling from the mitochondria malfunctions, the defect can cause cancer, she said. Cardiolipin may play a role in critical signaling pathways.
"The fact that you can study a disease that affects the human heart in a single-cell organism that lacks a heart and come up with relevant information is amazing," Claypool said.
Tafazzin's association with both the outer membrane and the inner membrane is consistent with its ability to modify a membrane component such as cardiolipin, Claypool said. Tafazzin might play a "surveillance" role in the mitochondria, the chemists said.
The research was funded by the American Heart Association and the National Institutes of Health. A co-author of the study, published in the July 31 issue of the Journal of Cell Biology (http://www.jcb.org), is J. Michael McCaffery of Johns Hopkins University's Integrated Imaging Center.
Koehler's laboratory studies mitochondrial diseases -- and how defects in mitochondrial function lead to disease -- by using model systems in which they can study the biochemistry in a way they cannot with humans. (Her research team also uses zebrafish as a model system.)
Mitochondria may play a more important role in human health than scientists and doctors have realized, Koehler believes.
Parkinson's appears to be a mitochondrial disease, she said. Types of blindness and deafness are caused by defects in mitochondria. Koehler's laboratory also is studying programmed cell death, or how a cell knows when to die. The pathways start in the mitochondria, she said.
As we age, our mitochondria become less efficient, which could lead to heart problems, as well as loss of hearing and vision, said Koehler, whose future research may help answer whether such health problems are caused by an inability to assemble mitochondria properly.
Is there a link between the deterioration of mitochondrial functioning that occurs as we age and the common problems many of the elderly have with hearing, vision, memory loss and decreased cardiac functioning?
"I think we should consider the possibility," Koehler said. "Any health concern that's an energy problem could be related to mitochondrial assembly. I hope my research will answer fundamental questions about these processes."
Mitochondria, which look very much like bacteria, are descendants of free-living bacteria, which the ancestors of today's cells captured about 1.5 billion years ago as energy-producing "slaves," Koehler said. Over time, the captives became integral parts of their hosts, transferring most of their DNA to the host nucleus. The tiny fraction of the DNA they retained can specify only a handful of the proteins. While a mitochondrion is made up of hundreds of different proteins, the vast majority of these are made outside the mitochondrion and then imported inside. Each imported mitochondrial protein has a specific "address" that is read by machinery for delivering proteins to their correct destination within the mitochondria. This machinery consists of many dozens of proteins and consumes a substantial amount of energy. How this machine works is not well-understood; discovering its mechanics is a major research goal of the research team.
Koehler conducts research in biochemistry, genetics and cell biology to study how mitochondria are assembled and function, how proteins enter the mitochondria and reach the right location inside, and how mitochondria communicate with the rest of the cell.
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