Mitochondrial base editing: from principle, optimization to application

In recent years, mitochondrial DNA (mtDNA) base editing systems have emerged as bioengineering tools. DddA-derived cytosine base editors (DdCBEs) have been developed to specifically induce C-to-T conversion in mtDNA by the fusion of sequence-programmable transcription activator-like effector nucleases (TALENs) or zinc-finger nucleases (ZFNs), and split deaminase derived from interbacterial toxins. Similar to DdCBEs, mtDNA adenine base editors have been developed with the ability to introduce targeted A-to-G conversions into human mtDNA. In this review, we summarize the principles of mtDNA base-editing systems and elaborate on the evolution of different platforms of mtDNA base editors, including their deaminase replacement, engineering of DddA_tox variants, structure optimization and editing outcomes. Finally, we highlight their applications in animal models and human embroys and discuss the future developmental direction and challenges of mtDNA base editors.