The laboratory of Dr. Marisol Corral-Debrinski has done excellent work demonstrating allotopic expression of three of the 13 mitochondrially encoded genes. (Research funded by SENS Foundation.) Expanding on the fantastic work from the Corral-Debrinski lab, the SENS Foundation Research Center in Mountain View, California is now attempting to extend that work to all 13 mitochondrially encoded genes.  In close collaboration with the Paris lab, we are working in cell culture to demonstrate allotopic expression, localization, and function of all 13 mitochondrially encoded genes.  It is an ambitious undertaking, but with the great success, both in cells and in preliminary gene therapy testing, of the genes already cloned and tested by the Paris group, we are optimistic about achieving rapid progress in this critical realm of SENS research. 

Along with mutations in our chromosomes, aging bodies also accumulate disabling "deletion" mutations in the separate DNA housed in the energy-producing mitochondria. In our research theme of MitoSENS, SENS Foundation has identified the placement of functioning "backup copies" of mitochondrial genes in the cell nucleus as a potential "engineering" solution to preempt the metabolic mayhem these mutations ultimately create.

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 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 French National Institute of Health and Medical Research (Inserm). 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.