Core Viewpoint - The article discusses significant advancements in mitochondrial DNA (mtDNA) editing technologies, particularly focusing on the development of efficient base editors that can potentially treat mitochondrial diseases and create animal models for research [2][4][12]. Group 1: Historical Context and Technological Development - The history of biotechnology is marked by key discoveries, including the first restriction enzyme in 1968, the invention of PCR in 1985, and the application of CRISPR technology in 2013, which have all enhanced the ability to manipulate DNA and treat genetic diseases [2]. - While CRISPR has achieved remarkable success in editing nuclear DNA (nDNA), progress in mtDNA editing has lagged behind, despite its critical role in cellular energy production and the severe diseases caused by mtDNA mutations [2]. Group 2: Recent Innovations in mtDNA Editing - In 2020, a team led by Liu Ruqian developed a base editor, DdCBE, that enables C-to-T editing of mtDNA, followed by a 2022 advancement by a South Korean team that achieved A-to-G editing using a modified version of DdCBE [3]. - However, the efficiency of existing A-to-G editing methods remains low, making it challenging to create mtDNA mutation animal models or to directly correct pathogenic mtDNA mutations in vivo [3]. Group 3: Breakthroughs in Base Editing - On June 3, 2025, research teams from East China Normal University and Lingang Laboratory published two papers in Nature Biotechnology, introducing a high-performance mitochondrial adenine base editor, eTd-mtABE, which significantly improves editing efficiency and reduces off-target effects [4][11]. - The eTd-mtABE demonstrated an editing efficiency of up to 87% in human cells and a 145-fold increase in editing efficiency in rat cells, enabling the creation of auditory neuropathy and Leigh syndrome rat models with high mutation frequencies [9][11]. Group 4: Implications for Disease Models and Treatments - The research teams successfully used eTd-mtABE to construct rat models for auditory neuropathy and Leigh syndrome, achieving a 74% efficiency in generating Leigh syndrome models that exhibited severe motor and cardiac dysfunction [11]. - An improved DdCBE variant was engineered to achieve an average of 53% restoration of wild-type mtDNA in Leigh syndrome models, leading to significant recovery of muscle and cardiac functions to wild-type levels [12]. Group 5: Future Prospects - The development of eTd-mtABE and the enhanced DdCBE variant represents a powerful tool for both basic and translational research in mitochondrial function and disease [12]. - The advancements in precise mtDNA editing highlight the potential for future applications in larger animal models and clinical settings, paving the way for innovative treatments for mitochondrial diseases [14].