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Mitochondria serve as energy-generating factories and as modulators for cellular homeostasis. Natural evolution moved most of the mitochondrial genome to the cell nucleus, except for 13 protein-coding genes and 24 non-coding genes, which aid protein translation in mammalian cells. Hundreds of potentially pathogenic variants of mitochondrial DNA (mtDNA) have been associated with mitochondrial diseases that generally manifest as severe conditions, which can often be fatal. No curative treatment is currently available for mitochondrial diseases due to the lack of suitable cellular and animal models. Recently, double-stranded-DNA deaminase (DDDA)-derived cytosine base editors (DDCBE) have been developed to catalyze site-specific C:G to T:T conversion in mtDNA.1, These base editors allow for the establishment of pathogenic mtDNA forms in cells, mice, zebrafish and rats.1,2,3,4,5, However, off-target edits detected in mitochondrial and nuclear genomes in these cellular and animal models raised concerns about the specificity of DdCBEs.2,3,4,5,6,7, Furthermore, cost and time constraints made individual establishment of hundreds of pathogenic variants in cells and animals a formidable challenge. Instead, knocking out mitochondrial protein-coding genes would be a viable option for modeling mtDNA dysfunction in vitro and in vivo. Reporting Nature Biomedical EngineeringMichal Minczuk and colleagues now describe a library of improved mitochondrial base editors that can be used to precisely and efficiently sequence each of 13 mitochondrial protein-coding genes.8,
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