Along with mutations in our chromosomes, aging bodies also accumulate disabling "deletion" mutations in the separate DNA housed in the energy-producing mitochondria. SENS Foundation has identified the placement of functioning "backup copies" of mitochondrial genes in the cell nucleus as an "engineering" solution to preempt the metabolic mayhem these mutations ultimately create. The Foundation is now funding the expansion of work in the lab of Dr. Marisol Corral-Debrinski at the Institut de la Vision at Pierre and Marie Curie University, Paris, who has developed the most promising method to achieve this goal for most, if not all, of the relevant mitochondrial genes.

The energy-harvesting mitochondria normally convert energy from dietary nutrients into the cell's energy currency (ATP) using a harnessed chemical reservoir, similar in principle to a hydroelectric dam, called the electron transport chain. Of the dozens of proteins that create the reservoir and link it to energy production, 13 are encoded in genes housed in the mitochondria themselves. Because ATP production creates toxic free radical wastes, the close proximity of the mitochondrial DNA to the ATP production site makes it highly vulnerable to being damaged, and it can acquire large deletion mutations. It has been proposed that the age-related accumulation of cells that have been entirely taken over by mitochondria harboring such deletions spreads oxidative stress throughout the body, damaging biological structures and dysregulating genes.

To solve this problem, functioning "backup copies" of genes that are normally housed in the mitochondria can in principle be placed in the nucleus, where they are substantially shielded from the constant, mutagenic free radical bombardment of the mitochondria themselves. With suitable modification, these genes can produce the proteins they encode from their new location (allotopic expression) and cause the resulting protein to be targeted into the mitochondria to restore normal energy production. Hoewever, some of the modifications needed for suitable targeting are difficult to identify.

Several approaches have been used and proposed to help allotopically-expressed proteins make their passage from where they are expressed in the main cell body into the mitochondria where they are used. The most successful so far has been an innovative method pioneered by Dr. Marisol Corral-Debrinski, now of the Institut de la Vision at Pierre and Marie Curie University, Paris. This method allows newly-synthesized proteins to thread their way efficiently into the access portals of the mitochondrial membranes by attaching signaling sequences to the working copies of the encoding instructions (their "messenger RNA") that target them to use protein-synthesis machinery closely associated with the mitochondrial membrane itself.

In light of these initial successes, SENS Foundation has funded the expansion of the Corral-Debrinski group's work, including an exciting proof-of-concept in which mutated and functioning genes for one of the subunits of the mitochondrial energy-producing machinery carrying this targeting sequence were introduced into the eyes of rats. While the mutated gene caused partial blindness in the affected eyes, allotopically-expressed normal proteins restored normal vision to the rats.

This important Foundation-funded work is currently on temporary hiatus, due to a fire that occurred in early 2009 in the campus housing Dr. Corral-Debrinski's lab, necessitating the complete re-equipping of the whole building. While renovation and restoration efforts are underway, the lab's work has continued in a limited way, dispersed across three other labs, providing a solid basis for moving forward once their facilities are back up and running. We anticipate a full resumption of this project during 2010.