Mitochondrial disorder treated by targeting nucleus

Mitochondria act like tiny generators inside our cells, but when they go wrong they may trigger a range of diseases. The root of the problem can lie in mutations in the DNA carried within mitochondria, which is distinct from the DNA in the cell's nucleus.

One such mitochondrial disorder is Leber's hereditary optic neuropathy (LHON), a rare cause of vision loss in young adulthood.

In LHON, problems arise with a protein assembly called Complex I, which is encoded in part by the DNA in mitochondria. The dysfunction leads to the death of retinal ganglion cells at the back of the eye.

Using gene therapy to fix glitches in mitochondrial DNA is challenging, not least because the therapy must be delivered to the many mitochondria in each cell. Now Jane Farrar at Trinity College Dublin, Ireland, and her colleagues have demonstrated a workaround. They target the cell's nucleus instead, encouraging it to produce Complex-I-type proteins, which then enter the many mitochondria in the cell. It's not a completely new approach, but the study shows how it can be applied in the eye relatively easily.

Farrar's team mimicked LHON in mice by giving them a drug that inhibits Complex I. Through an injection into the eye, they then used a virus to deliver a gene from yeast (Saccharomyces cerevisiae) into the nucleus of the rodent retinal ganglion cells. The gene, NDI1, codes for a protein that works like mammalian Complex I.

The gene was switched on within the nucleus and the protein it made appeared to compensate for dysfunctional Complex I in the rodent mitochondria.

"In theory the system should rescue Complex I deficiency no matter what mutation was causing the original defect," says Farrar ? although there are no guarantees that this kind of treatment will work as well in humans as in mice.

The study expands the possibility of developing a treatment for LHON, says Jean Bennett at the University of Pennsylvania in Philadelphia, who was not involved in the research.

"While there will likely be challenges encountered along the way ? including the potential of development of an immune response to the yeast protein ? the unequivocal successes in the small animal preclinical studies are encouraging."

Journal reference: European Journal of Human Genetics, DOI: 10.1038/ejhg.2012.112

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