N6-Deoxyadenosine Methylation in Mammalian Mitochondrial DNA

Ziyang Hao, Tong Wu, Xiaolong Cui, Pingping Zhu, Caiping Tan, Xiaoyang Dou, Kai Wen Hsu, Yueh Te Lin, Pei Hua Peng, Li Sheng Zhang, Yawei Gao, Lulu Hu, Hui Lung Sun, Allen Zhu, Jianzhao Liu, Kou Juey Wu, Chuan He*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

151 Scopus citations


N6-Methyldeoxyadenosine (6mA) has recently been shown to exist and play regulatory roles in eukaryotic genomic DNA (gDNA). However, the biological functions of 6mA in mammals have yet to be adequately explored, largely due to its low abundance in most mammalian genomes. Here, we report that mammalian mitochondrial DNA (mtDNA) is enriched for 6mA. The level of 6mA in HepG2 mtDNA is at least 1,300-fold higher than that in gDNA under normal growth conditions, corresponding to approximately four 6mA modifications on each mtDNA molecule. METTL4, a putative mammalian methyltransferase, can mediate mtDNA 6mA methylation, which contributes to attenuated mtDNA transcription and a reduced mtDNA copy number. Mechanistically, the presence of 6mA could repress DNA binding and bending by mitochondrial transcription factor (TFAM). Under hypoxia, the 6mA level in mtDNA could be further elevated, suggesting regulatory roles for 6mA in mitochondrial stress response. Our study reveals DNA 6mA as a regulatory mark in mammalian mtDNA.

Original languageEnglish
Pages (from-to)382-395.e8
JournalMolecular Cell
Issue number3
StatePublished - 07 05 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.


  • METTL4
  • N-methyldeoxyadenosine (6mA)
  • TFAM
  • methyltransferase
  • mitochondrial DNA methylation
  • mitochondrial replication
  • mitochondrial transcription regulation


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