Recent advancements in mitochondrial genome editing technologies take scientists one step closer to developing viable treatments for mitochondrial diseases, which affect 1 in 4300 adults.
ADDITIONAL MEDIA NOTES
There is strength in numbers — or at least the right proportion. A new study from University of Miami Miller School of Medicine researchers demonstrates an ability to target and reduce debilitating high levels of mutant mitochondrial DNAin heart and other muscle tissue to an extent — so far in mice — that could be curative.
The findings offer hope to people living with relatively rare mitochondrial diseases, such as Kearns-Sayre syndrome, progressive external ophthalmoplegia, myoclonus epilepsy with ragged-red fibers, and Pearson’s syndrome.
The DNA inside mitochondria — the “power plants” that generate energy in most cells and allow proper functioning — is present in multiple copies, and mutations cause diseases only when present in the vast majority of these molecules. People with high levels of mutated mitochondrial DNA (mtDNA) can experience muscle weakness, developmental delays, seizures, and other serious adverse effects.
For years, researchers have searched for an effective way to reduce the high number of mutant mtDNA molecules in critical organs, like the heart, and in skeletal muscle.
In a new study published in Nature Medicine, Carlos T. Moraes, Ph.D., professor of neurology and cell biology, and the Esther Lichtenstein Chair in Neurology, lead author Sandra R. Bacman, Ph.D., associate scientist in the Department of Neurology, and their colleagues offer a promising way to accomplish precisely that. READ MORE.
CRISPR, the genome editor celebrated as a potentially revolutionary medical tool, isn’t omnipotent. Mitochondria, the organelles that supply a cell’s energy, harbor their own mitochondrial DNA (mtDNA) and mutations there can have devastating consequences including deafness, seizures, and muscle weakness. Genome editing might be a remedy, but mitochondria appear to be off-limits to CRISPR.
Now, two studies published this week in Nature Medicine reveal that two older genome-editing tools can slash the amount of defective mtDNA in mice bred to have a mitochondrial disease, counteracting the effects of the mutation. The proof-of-principle results could open the way for the first treatments for mitochondrial diseases. “These are remarkable findings that make it possible to even consider doing this in humans,” says mitochondrial biologist Martin Picard of the Columbia University Irving Medical Center, who was not involved in the work.
The inner mitochondrial membrane ATPase family AAA domain-containing protein 3 (ATAD3) has several cellular roles, as shown in numerous organisms. In their Research Article (Peralta et al., 2018), Carlos Moraes and colleagues use a mouse strain with a conditional knockout that is specific to skeletal muscles to address the in vivo role of ATAD3. They find that loss of ATAD3 in muscles leads to progressive myopathy after 2-3 months in these mice. Furthermore, the cristae structure of mitochondria is disrupted and the surface area of cristae decreased. In absence of ATAD3, protein levels of the cristae biogenesis complex mitochondrial contact site and cristae organising system (MICOS) are reduced. The authors show that this, in turn, leads to changes in cholesterol metabolism, depletion of mitochondrial DNA (mtDNA) and impaired mtDNA replication. Interestingly, ATAD3 is not crucial for mitochondrial translation, since the observed decrease of levels in oxidative phosphorylation (OXPHOS) complex members occurs after the defect in cristae appearance. This work establishes the in vivo function of ATAD3 as mediating the ultrastructure of mitochondria and the control of key regulators of cristae morphology, such as MICOS, and, subsequently, the mtDNA replication process and metabolism.
Mitochondrial Myopathies – Carlos T. Moraes, PhD
“There are no treatments for mitochondrial diseases. The unique genetics of mitochondria offer some opportunities for genetic manipulation that could be curative. Our approach has the potential to be curative. The main limitation will be delivery systems for the DNA editing enzyme, which are being developed at a fast pace.”
Carlos T. Moraes, professor of Neurology at the University of Miami’s Miller School of Medicine in Florida, was awarded an MDA Research Grant totaling $300,000 over 3 years to study monomeric gene-editing enzymes to treat mitochondrial myopathies.
Mitochondrial diseases caused by mutations in the mitochondrial DNA (mtDNA) are most often heteroplasmic, meaning that the normal mtDNA coexists with the mutant mtDNA. Disease is manifested when the cells/tissue have a very high percentage of mutant mtDNA. There are no treatments for mitochondrial diseases, but the unique genetics of mitochondria offer some opportunities for genetic manipulation that could be curative.
With previous MDA funding, Dr. Moraes and colleagues have developed approaches to reduce the percentage of mutant mtDNA using DNA-editing enzymes, but the feasibility of this approach is limited because these enzymes are difficult to deliver to affected tissues. Therefore, he has developed an innovative approach to improve the delivery of gene-editing components to mitochondria, and in this project will test the success in different animal models, improving the chances of bringing this approach to the clinics.
Carlos T. Moraes, Ph.D., professor of neurology and cell biology at the University of Miami Miller School of Medicine, was honored with the presentation of the Esther Lichtenstein Chair in Neurology. In his 20 years at the Miller School, Moraes has made significant advancements in understanding the cellular mechanisms behind degenerative neurological conditions, such as Parkinson’s and Alzheimer’s disease. Read more here.
Carlos T. Moraes, Ph.D., receives the Esther Lichtenstein Chair in Neurology, with, from left, Pascal J. Goldschmidt, M.D., Walter G. Bradley, D.M., F.R.C.P., Carlos T. Moraes, Ph.D. and Ralph L. Sacco. M.D., M.S.