MitoSENS: Preventing damage from mitochondrial mutations
Accumulation of mutations in mitochondrial DNA is recognized as a significant consequence of aging and is implicated in the metabolic derangement of aging and in accelerating the course of the degenerative aging process as a whole. Mutations in the mitochondrial genes occur as a consequence of constant exposure to reactive oxygen species resulting from the mitochondrial energy generation process. Because mitochondria lack an efficient repair mechanism, these mutations accumulate over time and compromise respiratory chain function and hence energy generation. One need only look at the mitochondrial genetic diseases to see the similarities to many of the diseases and maladies of aging. For example, mutations in ND1 have been implicated in the development of Parkinson’s disease, and Cytochrome B (CYB) mutations can cause muscle fatigue/ exercise intolerance in young patients.
Allotopic Expression
The essential strategy we are using in our approach to MitoSENS is to render the mitochondrial genome redundant. The plan is to engineer versions of the 13 protein-encoding mitochondrial genes involved in respiratory chain function (out of a total of 37 mitochondrial genes) that will be suitable for expression from the cell nucleus and for subsequent delivery of their protein products into the mitochondria. We will then use gene therapy to insert these modified mitochondrial genes into the nuclear genome of the cell and validate the targeting and functional importation of these ‘allotopically-expressed’ proteins into the mitochondria.
Previous attempts at allotopic expression have experienced only limited success due to problems with import of the proteins into the mitochondria, which were likely caused by the hydrophobic nature of the proteins. In addition to being ineffective, incomplete protein import is likely toxic to the mitochondrion and ultimately to the cell. To sidestep these problems and achieve optimal mitochondrial import, a co-translational import strategy will be used. This strategy has been successfully employed by Professor Corral-Debrinski in work previously funded by SENS Research Foundation. The improvement that Dr. Corral-Debrinski has pioneered is to tag the RNA of the genes with sequences that not only target the proteins to the mitochondria, but direct the RNA to the mitochondrial surface before it is translated into protein. This approach prevents the convoluted folding of these proteins during translation in the watery environment of the cytosol, improving the efficiency of protein import.
Using mitochondrial gene therapy as a strategy to correct mitochondrial dysfunction has many advantages. In theory, such gene therapy could be used both to prevent and to correct the effects of mitochondrial mutations. Another exciting potential is that any therapy we develop could, in principle, be used to treat any of the known diseases of the mitochondria, such as LHON (Leber Hereditary Optic Neuropathy), Leigh syndrome, and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa), all of which are debilitating diseases. Indeed, allotopic expression is already being tested in human clinical trials to treat LHON. Treatment of these known and well-characterized diseases is a licensable therapeutic indication under current regulation, which therefore constitutes an entry point for the first human uses of mitochondrial gene therapies that emerge from our work. This foundation, and the experience of patients treated with allotopically-expressed mitochondrial genes for mitochondriopathies, will give rejuvenation researchers an excellent opportunity to develop mitochondrial gene therapies for use against the systemic metabolic derangement imposed by age-related mitochondrial mutation.
