ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing

Nat Cell Biol. 2021 Jul;23(7):684-691. doi: 10.1038/s41556-021-00709-7. Epub 2021 Jul 12.


Members of the mammalian AlkB family are known to mediate nucleic acid demethylation1,2. ALKBH7, a mammalian AlkB homologue, localizes in mitochondria and affects metabolism3, but its function and mechanism of action are unknown. Here we report an approach to site-specifically detect N1-methyladenosine (m1A), N3-methylcytidine (m3C), N1-methylguanosine (m1G) and N2,N2-dimethylguanosine (m22G) modifications simultaneously within all cellular RNAs, and discovered that human ALKBH7 demethylates m22G and m1A within mitochondrial Ile and Leu1 pre-tRNA regions, respectively, in nascent polycistronic mitochondrial RNA4-6. We further show that ALKBH7 regulates the processing and structural dynamics of polycistronic mitochondrial RNAs. Depletion of ALKBH7 leads to increased polycistronic mitochondrial RNA processing, reduced steady-state mitochondria-encoded tRNA levels and protein translation, and notably decreased mitochondrial activity. Thus, we identify ALKBH7 as an RNA demethylase that controls nascent mitochondrial RNA processing and mitochondrial activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • AlkB Enzymes / genetics
  • AlkB Enzymes / metabolism*
  • Cytidine / analogs & derivatives
  • Cytidine / metabolism
  • Guanosine / analogs & derivatives
  • Guanosine / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Mitochondria / enzymology*
  • Mitochondria / genetics
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Protein Biosynthesis
  • RNA Processing, Post-Transcriptional*
  • RNA, Mitochondrial / genetics
  • RNA, Mitochondrial / metabolism*
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism


  • Mitochondrial Proteins
  • RNA, Mitochondrial
  • Guanosine
  • 1-methyladenosine
  • 3-methylcytidine
  • 1-methylguanosine
  • N(2),N(2)-dimethylguanosine
  • Cytidine
  • RNA, Transfer
  • ALKBH7 protein, human
  • AlkB Enzymes
  • Adenosine