Correcting Human Mitochondrial Mutations
For the first time, a way has been found to correct mutations in human mitochondrial DNA by targeting corrective RNAs
Mutations in the human mitochondrial genome are implicated in neuromuscular diseases, metabolic defects and aging.
Currently there are no methods to successfully repair or compensate for these mutations, according to study co-senior author Dr. Michael Teitell, a professor of pathology and laboratory medicine and a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles (UCLA).
Between 1,000 and 4,000 children per year in the United States are born with a mitochondrial disease and up to one in 4,000 children in the U.S. will develop a mitochondrial disease by the age of 10, according to Mito Action, a nonprofit organization supporting research into mitochondrial diseases.
In adults, many diseases of aging have been associated with defects of mitochondrial function, including diabetes, Parkinson's disease, heart disease, stroke, Alzheimer's disease and cancer.
"I think this is a finding that could change the field," Teitell said. "We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans."
The study appears March 12, 2012 in the peer-reviewed journal Proceedings of the National Academy of Sciences.
The current study builds on previous work published in 2010 in the peer-reviewed journal Cell, in which Teitell, Carla Koehler, a professor of chemistry and biochemistry and a Broad Stem Cell Research Center scientist, and their team uncovered a role for an essential protein that acts to shuttle RNA into the mitochondria - the energy-producing "power plant" of a cell.
Mitochondria are described as cellular power plants because they generate most of the energy within a cell. In addition to creating energy, mitochondria also are involved in signaling and control of the cell cycle and growth.
Importing nucleus-encoded small RNAs into mitochondria is essential for replicating, transcribing and translating mitochondrial genes, but the mechanisms for how RNA is imported into mitochondria have remained poorly understood.
The 2010 study outlined a new role for a protein called polynucleotide phosphorylase (PNPASE) in regulating the import of RNA into mitochondria. Reducing PNPASE decreased the import of RNA, which impaired the processing of mitochondrial RNAs.
Reduced mitochondrial RNA went on to inhibit the translation of proteins regulating oxygen needed in energy production. With reduced PNPASE, protein translation was inhibited and energy production was compromised, stalling cell growth.
The findings from the current study provide a form of gene therapy for mitochondria by compensating for mutations that cause a wide range of diseases, said study co-senior author Koehler.
Gene therapy is often sought after to express proteins to treat causes for a particular disease. In the case of PNPASE, post-doctoral fellow Geng Wang targeted the import of specific RNA molecules in the nucleus for import into the mitochondria and, once there, those RNA molecules to express proteins needed to repair mitochondrial gene mutations.
Koehler: "This [study] opens up new avenues to understand and develop therapies for mitochondrial diseases. This has the potential to have a really big impact. We just have to get it to the next step.
This study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with PNPASE, with or without a mitochondrial localization sequence, to provide an exciting, general approach for overcoming mitochondrial genetic disorders."
Going forward, Teitell and Koehler will test their new method in small animal models to determine whether they can fix a mitochondrial defect as it occurs in a whole organism.
One potential use for the new method would also be to repair mitochondrial defects in reprogrammed, embryonic or adult-type stem cells for use in regenerative medicine therapies.
The one-year study was supported by the California Institute of Regenerative Medicine, the National Institutes of Health, the American Heart Association and the Broad Stem Cell Research Center at UCLA.
The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding human adult and embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit our web site at http://www.stemcell.ucla.edu.
Original article: http://www.eurekalert.org/pub_releases/2012-03/uoc--chm030912.php