![]() The specific elimination of pathogenic mtDNA is followed by repopulation with normal mitochondrial DNA via heteroplasmy. ![]() Research on mitochondrial DNA editing started with the use of restriction endonucleases, such as PstI, SmaI, and ApaLI, engineered to be expressed exclusively in mitochondria (called mitoRes) 22, 23, 24. The development of and advances in base editing technology for correcting mtDNA base variants promise a potential therapeutic strategy for mitochondrial diseases and the generation of disease models in living cells and animals.įull size image The development of and advances in mitochondrial gene editing tools Although single-base substitutions can theoretically be corrected using base editors, precise and efficient therapeutics for several mtDNA mutations and mitochondria-involved diseases, have not been reported thus far. Strikingly, the C5024T mutation in the mtDNA gene MT-TA was uncovered via mouse models of heteroplasmic mitochondrial defects in the smooth muscle surrounding the colon and cardiomyocytes 21. Myoclonus epilepsy and ragged-red fiber (MERRF) syndrome, a severe neurodegenerative defect, is predominantly caused by the point mutation m.8344 A > G in the MT-TK gene 19. Meanwhile, three major mtDNA mutations, m.3460 G > A, m.11778 G > A, and m.14484 T > C, are present in more than 95% of patients suffering from Leber hereditary optic neuropathy (LHON), a maternally inherited disease that is associated with a loss of vision 17, 18. For instance, the MT‑TL1 mutation m.3243 A > G can trigger multiple mitochondrial syndromes, such as chronic progressive external ophthalmoplegia (CPEO) maternally inherited diabetes and deafness (MIDD) and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Notably, among the 97 known pathogenic mtDNA variants, point mutations accounted for 92 variants (approximately 95%), which indicated transition point mutations, including A > G, T > C, G > A, and C > T, accounting for 87% (MITOMAP: A Human Mitochondrial Genome Database. Specifically, a vast array of more than 250 mitochondrial defects have been implicated in various pathogenic mtDNA variants that primarily affect muscle and nervous tissues 15, 16. The exceeded heteroplasmic threshold of mtDNA mutations manifests in multiple disorders (Fig. Human mtDNA, with a few hundred to several hundred thousand copies contained in each cell 11, 12, encodes 37 genes (22 tRNAs, 2 rRNAs, and 13 oxidative phosphorylation protein subunits) in a small circular 16.5 kb double-stranded piece of DNA 13, 14. The mitochondrial genome is independent and distinct from that of the nucleus 10. Mitochondria, double membrane-bound organelles referred to as the “powerhouses of the cell”, play an indispensable role in eukaryotic cells, as they are associated with metabolism 1, 2 and orchestrate a variety of other cellular functions, such as apoptosis, cell pluripotency, autophagy, calcium homeostasis, and innate immunity 3, 4, 5, 6, 7, 8, 9.
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