YOU stick an address on a letter to tell it where to go 鈥� so why not do the same for proteins? A clever bit of 鈥渕olecular addressing鈥� might correct mitochondrial diseases, and perhaps even delay ageing.
Mitochondria are often referred to as the power plants of the cell because they perform most of the chemical reactions that transform sugars into usable energy. However, mutations in the genes that control this process are common. Mitochondrial diseases affect at least 1 in 5000 people and can lead to a variety of serious, incurable , including disorders of the nervous system and blindness. The gradual accumulation of mutations in mitochondria over a lifetime could also be an important cause of ageing.
Many of the genes responsible for energy production are made up of mitochondrial DNA, rather than DNA in the cell鈥檚 nucleus 鈥� and an obvious solution to mitochondrial errors would be to introduce a normal copy of the defective gene into the mitochondrial DNA. However, so far researchers have been unable to transport genes across the mitochondrial membrane into the mitochondria themselves. If they insert the gene elsewhere in the cell, the protein it codes for will often fail to fold correctly and thus cannot do its job.
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To solve this problem, Marisol Corral-Debrinski and her colleagues at the Pierre and Marie Curie University in Paris, France, picked two mitochondrial gene mutations: one that causes a syndrome characterised by muscle weakness, lack of co-ordination and retinal problems, and another which is responsible for a form of blindness called Leber hereditary optic neuropathy (LHON).
The team then tagged normal versions of these genes with two separate cellular 鈥渁ddress codes鈥� and inserted them into the cytoplasm of cells grown in a lab dish. The first code directs the messenger RNA 鈥� the molecule that carries the instructions for making a protein 鈥� to the surface of the mitochondria, ensuring that the protein gets made at the mitochondrial membrane. The second address code, known as the mitochondrial targeting sequence, tells the protein to enter the mitochondria. Researchers have previously tried using one or the other of these tags, but not both. 鈥淭o get the best result, you need both of them combined,鈥� says Corral-Debrinski.
Sure enough, these double-tagged genes were able to completely reverse the effect of both mitochondrial mutations in the cell cultures for up to a year (Rejuvenation Research, ).
鈥淒ouble-tagged genes were able to reverse the effect of both mitochondrial mutations in cell cultures for up to a year鈥�
鈥淚t鈥檚 a really smart idea,鈥� says Eric Schon, a mitochondrial researcher at Columbia University in New York. However, he adds, 鈥渋t鈥檚 [only] the next step in the long, hard slog to getting this to work perfectly鈥�.
Corral-Debrinski is now planning to test the gene therapy on lab rats.
As ever with gene therapy, before the technique can be transformed into a useful human treatment, researchers will have to find a way to get the normal genes to the right parts of the body safely without causing harmful side effects on other tissues.
However, LHON may be easier to treat with gene therapy than most diseases, says Corral-Debrinski, because the eye is well isolated. This means that you can inject small quantities of the gene construct into the eye, and it won鈥檛 become distributed all over the body, she says.
If all the problems can be solved, double-tagging genes may also provide a way of introducing other proteins into mitochondria to stop some of the effects of ageing. For example, researchers might like to insert antioxidant enzymes to see if reducing oxidative damage to mitochondrial DNA will lead to fewer mutations, which could in turn delay ageing, Schon says.
