Joseph Baur, PhD| University of Pennsylvania
Competition Sponsor: US National Academy of Medicine
Awardee Year: 2022
Mitochondria, the “powerhouses of the cell” contain their own genomes that are present in hundreds of copies per cell and are prone to mutation. Over the course of aging, some cells end up with a high fraction of their mitochondrial genomes (“mtDNA”) mutated, leading them to become dysfunctional. Inheriting mutated mtDNA through the germline causes primary mitochondrial disorders – devastating conditions with an array of symptoms that include a shortened life expectancy. Whether the number of cells affected by mtDNA mutation during normal aging is sufficient for it to be a true “driver” of the aging process is debated, but accelerating mutation accumulation shortens mouse lifespan. At present, there is no viable strategy to eliminate mutant mtDNAs, either in disease or during normal aging. We propose that it might be possible to selectively block replication of mutant mtDNAs taking advantage of modified nucleic acids that bind more tightly than natural DNA in a sequence-specific way. By conjugating these nucleic acids to a delivery vehicle that can enter cells and reach the mitochondria, a purifying selection may be imposed to favor wild type mtDNA and restore cell function. We will test this approach in vitro and then in well characterized cell lines containing a mix of wild type and mutant mtDNA. If successful, these experiments would lay the groundwork for efforts to eliminate mutant mtDNA in vivo.
To learn more about this proposal, email healthylongevity@nas.edu.