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Pierre and Marie Curie University

Nuclear Genes, Mitochondrial Proteins

Principal Investigator: Marisol Corral-Debrinski

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 Research 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 formerly of Pierre and Marie Curie University in Paris, 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.
Dr. Corral-Debrinski chose to move on to performing clinical trial in macular degeneration in work unrelated to our SENS Research mission, she provided a sufficiently strong foundation for the development of allotopic expression that we are able to continue this valuable work within our intramural program.