Designer enzymes tackle mutations in mitochondrial DNA

August 5, 2013 § Leave a comment

TALENs have developed that specifically target and remove mutations in mitochondrial DNA. Image provided by Carlos Moraes.

When a power station has trouble generating electricity, the town suffers. Cells are no different: When mitochondria struggle to generate ATP, cells suffer from a class of diseases called mitochondrial disorders.

Some of these diseases stem from a tug-of-war between mutated and healthy forms of the DNA that coexist in mitochondria. An example of a disease caused by mitochondrial DNA mutation is Leber optic neuropathy, in which adults experience unexpected vision loss.

In a paper just out in the journal Nature Medicine, researchers report that they have developed a method that deletes specific mutant mitochondrial DNA in human cells and shifts the war in favor of the healthy mitochondrial DNA.

The team led by Carlos Moraes at the University of Miami Miller School of Medicine used special designer enzymes called TALENs, an acronym for transcription activatorlike effector nucleases. These enzymes can be engineered to recognize any DNA sequence.

Moraes and colleagues created TALENs that could enter the mitochondria of cultured human cells  and identify  two different mutant mitochondrial DNAs from healthy DNAs. One mutated type contained a point mutation, and the other had with a deletion; both mutations are associated with human diseases. The authors demonstrated that the TALENs reduced the levels of mutant mitochondrial DNA and restored the normal energy-producing capacity.

“This approach, in my opinion, is the best chance to treat mitochondrial diseases that occur when there is both healthy and mutated DNA in the organelles,” says Moraes. “By eliminating, or just reducing, the levels of the mutated mitochondrial DNA, the wild-type DNA can compensate and repopulate the organelles. This can restore mitochondrial oxidative phosphorylation function and normal ATP production.”

However, Moraes cautions that the technique has not yet been tested in humans. The investigators are working on extending the method to animal models.

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