From the SENS3 conference via the Methuselah Foundation blog, several researchers presented their recent work aimed at advancing this and other potentially useful approaches to mitochondrial damage.
Mitochondrial damage is one of seven kinds of damage resulting from aging which if the damage was prevented or greatly reduced or repaired could result in lifespans increasing by several decades.
Dr. de Grey first proposed an ‘engineering’ solution to this form of aging damage in 1998: the use of allotopic expression — the creation of ‘backup copies’ of those genes in the safer confines of the nucleus — in 1998
PhD candidate Mark Hamalainen of Cambridge University presented the initial success in his Methuselah Foundation-funded work on allotopic expression, showing evidence that his allotopically-expressed genes could encode the relevant proteins and that these were taken up into the mitochondria. In this case, the genes encode healthy and defective versions of the protein that is miscoded in Neuropathy, Ataxia and Retinitis Pigmentosa (NARP), a hereditary mitochondrial disease characterized by blindness and weak and uncoordinated muscles.
Now Dr. Corral-Debrinski has leapt forward into a living organism, inserting an allotopic version of the defective human gene that causes the mitochondrial disease Leber Hereditary Optic Neuropathy (LHON) into mice retinas. The technique involves shifting the production site of such proteins closer to the mitochondria themselves, allowing the cell’s machinery to thread the proteins through the narrow straits of the mitochondria’s import channels as quickly as they are produced. Dr. Corral-Debrinski next hopes to take this to the next level, and cure the disease in mice by introducing the healthy gene.
Finally, Dr. Samit Adhya of the Division of Molecular and Human Genetics at the Indian Institute of Chemical Biology is pursuing yet another innovative approach. He proposes to dispense with the need for mitochondrial DNA altogether, by instead providing the mitochondrial protein-making machinery directly with the “working instructions” (messenger RNA) that it normally receives in the form of a transcribed copy taken from the mitochondrial DNA originals. This would allow the mitochondria to continue their protein production even if the mitochondrial DNA were completely destroyed: they would still have their marching orders, even if the general himself were incommunicado. Dr. Adhya is accomplishing this goal by borrowing a trick used by a single-celled organism called Leishmania tropica.
While we can’t yet draw definitive conclusions, all of Dr. Adhya’s results are consistent with success. In some of the most visually arresting presentations of the conference, Dr. Adhya showed how injecting the RIC-linked antisense RNA into the legs of rats quickly caused the same kind of leg muscle degeneration seen in MERRF; when examined under a microscope, muscle cells from such animals showed the death of muscle fibers and the loss of mitochondrial function.
The next step will be to introduce functional RNA into animals with dysfunctional mitochondrial genes. If this restores normal mitochondrial function and blocks the symptoms and pathology associated with the disease, we’ll know for sure that the RNA import technology works. This would allow us to sidestep not only the mutations in the mitochondrial DNA of those rare and unfortunate souls who suffer with congenital mitochondrial diseases, but those responsible for the universal mitochondrial failures of aging.
Several methods look like they are on track to repairing mitochondria.
Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
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