Genome editing in mitochondria: past, present and future
Speaker: dr Michał Mińczuk (MRC Mitochondrial Biology Unit, University of Cambridge)
Talk: Genome editing in mitochondria: past, present and future
Time: 06 March 2020, 9:00 am
Venue: Intercollegiate Faculty of Biotechnology, Abrahama 58, hall 042
Mitochondria are essential for human life. They are complex, compartmentalised organelles that form a dynamic network throughout the cell, host crucial metabolic processes vital for energy provision, and are central to cell fate decisions. Mitochondria contain multiple copies of their own genome, the mtDNA, that encodes the core subunits of the oxidative phosphorylation system. Mutations in protein or RNA coding genes of mtDNA are the most frequent cause of mitochondrial disease. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. In most cases, mutant and wild-type mtDNAs coexist within a single cell, resulting in heteroplasmy. The selective elimination of mutant mtDNA, and consequent enrichment of wild-type mtDNA, can rescue pathological phenotypes in heteroplasmic cells. In our work, we have developed mitochondrially targeted zinc finger-nucleases (mtZFNs) for degradation of mutant mtDNA through site-specific DNA cleavage. We have successfully used mtZFNs to target and cleave mtDNA harbouring disease-associated point mutations or large-scale deletions in vitro. More recently, we exploited a unique mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNAAla mouse. Through application of mtZFN delivered systemically by adeno-associated virus (AAV), we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These recent findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin.