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<p>Mitochondrial epigenetic editing offers a potential strategy for modulating disease-causing mitochondrial genes while leaving the underlying DNA sequence unchanged. In this study, we present MEE, a mitochondrial epigenetic editor consisting of mitochondrion-targeted TALE modules fused to <i>Dnmt3A</i> and <i>Dnmt3L</i> methyltransferases. MEE efficiently directed site-specific 5mC methylation within cellular mitochondrial DNA with low detectable off-target activity under the tested conditions. MEE-mediated methylation at the C12191 (H) site exceeded 53% and was associated with an approximately 95% reduction in steady-state MT-ND5 mRNA levels in human cells. Notably, MEE increased methylation at the aging-associated C11168 (H) site by 11.76% in vivo, leading to reduced MT-ND4 expression in the targeted brain region and altered plasma levels of t-Tau and NFL in mice. These findings demonstrate that MEE provides a tool for precise epigenetic engineering of mitochondrial DNA, enabling experimental interrogation of specific 5mC modifications and exploration of the functional roles of mitochondrial DNA methylation in aging-associated diseases.</p>

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Programmable aging function-related mitochondrial DNA 5-methylcytosine (m5C) modification with a TALE-directed methyltransferase

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月27日

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  • Guo Li,
  • Xinzhi Zhou,
  • Guanglin Zhu,
  • Yaxian Cheng,
  • Yingjia Pan,
  • Xiaomeng Guo,
  • Guoya Liao,
  • Xiangyang Li,
  • Xiaoxiang Hu,
  • Yuan Yao,
  • Zhimin Gu,
  • Wen Jiang

摘要

Mitochondrial epigenetic editing offers a potential strategy for modulating disease-causing mitochondrial genes while leaving the underlying DNA sequence unchanged. In this study, we present MEE, a mitochondrial epigenetic editor consisting of mitochondrion-targeted TALE modules fused to Dnmt3A and Dnmt3L methyltransferases. MEE efficiently directed site-specific 5mC methylation within cellular mitochondrial DNA with low detectable off-target activity under the tested conditions. MEE-mediated methylation at the C12191 (H) site exceeded 53% and was associated with an approximately 95% reduction in steady-state MT-ND5 mRNA levels in human cells. Notably, MEE increased methylation at the aging-associated C11168 (H) site by 11.76% in vivo, leading to reduced MT-ND4 expression in the targeted brain region and altered plasma levels of t-Tau and NFL in mice. These findings demonstrate that MEE provides a tool for precise epigenetic engineering of mitochondrial DNA, enabling experimental interrogation of specific 5mC modifications and exploration of the functional roles of mitochondrial DNA methylation in aging-associated diseases.