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Comment
. 2020 Oct 8;383(15):1489-1491.
doi: 10.1056/NEJMcibr2025332.

Editing the Mitochondrial Genome

Maria Falkenberg  1 , Michio Hirano  1
Affiliations
Comment

Editing the Mitochondrial Genome

Maria Falkenberg et al. N Engl J Med. .
No abstract available

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Figures

Figure 1.
Figure 1.. New Tools for Editing the Mitochondrial Genome.
For most disease-causing mutations in mitochondrial DNA (mtDNA), the level and tissue distribution of heteroplasmy determines the phenotypic manifestations (Panel A). A typical human cell contains more than 1000 mtDNA copies, and the presence of mutations in a substantial fraction of these typically has few or no ill effects. Reduced oxidative phosphorylation activity and disease phenotypes are not observed until the level of mutated mtDNA exceeds a specific threshold. Genome editing can correct mtDNA mutations and thereby shift the heteroplasmy levels below the threshold required for disease phenotypes to occur. With the use of a base editor derived from an interbacterial toxin called DddA (DddA-derived cytosine base editor [DdCBE]), mtDNA can be edited directly (Panel B). The cytidine deaminase domain of the toxin (DddATOX) is split into two inactive parts, each fused to an engineered sequence-specific DNA-binding domain (here, a transcription activator–like effector [TALE]). When the TALE constructs bind to adjacent DNA sequences, the DddATOX halves align, forming an active deaminase. The deamination of C to U in mtDNA leads to the formation of a UG base pair. Uracil glycosylase inhibitors (UGIs) prevent mtDNA repair machinery from removing the U. During the next round of mtDNA replication, U bonds with A, which eventually leads to the conversion of a CG to a TA base pair.
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Comment on

References

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    1. Mok BY, de Moraes MH, Zeng J, et al. A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature 2020; 583: 631–7. - PMC - PubMed

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