Targeting RNA for Mitochondrial Mutation Repair

Mitochondrial diseases affect 1,000 to 4,000 newborn children each year in the US1.  These diseases often result in loss of muscle coordination, muscle weakness, poor growth, visual and hearing problems, learning disabilities, neurological disorders and dementia.  They are most often caused by mutations in the mitochondrial DNA.

Mitochondrial DNA is more susceptible to mutation than nuclear DNA because its repair functions are less robust and are more vulnerable to oxidative damage due to its proximity to the respiratory chain.  Researchers have identified a protein that may be key in developing a gene therapy for mitochondrial disease.

In 2010, Teitell and Koehler identified the protein called polynucleotide phosphorylase (PNPASE), which is involved in the regulation of transporting RNA into the mitochondria.  The importation of RNA into the mitochondria is necessary for the replication, transcription, and translation of the mitochondrial genome.  Therefore, with the decreased expression of PNPASE, the import of RNA into the mitochondria also reduces and ultimately leads to the halt of cell growth.  A subsequent study, "Correcting human mitochondrial mutations with targeted RNA import," explores the use of PNPASE to import specific RNA molecules into the mitochondria, which express the production of other proteins capable of repairing the mutated mitochondrial genome.

Geng Wang and colleagues developed a method to pinpoint and import specific RNA molecules into the mitochondria to regulate proteins essential for the repair gene mutations.  The reparative RNA molecules that Wang was targeting exist in the nucleus of the cell.  First a series of export sequences were engineered to direct the reparative RNA out of the nucleus and into the mitochondria.  Once inside the mitochondria, the targeted RNA were able to repair mutated mitochondrial DNA as was demonstrated in two different human cell line models of mitochondrial disease.

Researchers are now hopeful that this strategy for correcting mitochondrial mutations can be demonstrated in animal models.  If successful this method could also be applied to the development of regenerative medicine therapies by repairing mitochondrial mutations in stem cells.