ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing

Members of the mammalian AlkB family are known to mediate nucleic acid demethylation1,2. ALKBH7, a mammalian AlkB homologue, localizes in mitochondria and affects metabolism(3), but its function and mechanism of action are unknown. Here we report an approach to site-specifically detect N-1-methyladenosine (m(1)A), N-3-methylcytidine (m(3)C), N-1-methylguanosine (m(1)G) and N-2,N-2-dimethylguanosine (m(2)(2)G) modifications simultaneously within all cellular RNAs, and discovered that human ALKBH7 demethylates m(2)(2)G and m1A within mitochondrial Ile and Leu1 pre-tRNA regions, respectively, in nascent polycistronic mitochondrial RNA(4,5,6). 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.

Automated summary

ALKBH7 is identified as an RNA demethylase that controls nascent mitochondrial RNA processing and mitochondrial activity, with depletion leading to increased processing of polycistronic mitochondrial RNA, reduced levels of mitochondria-encoded tRNA and protein translation, as well as decreased mitochondrial activity.