Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial
oxidative RNA demethylation
ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing.
Members of the mammalian AlkB family are known to mediate nucleic acid demethylation<sup>1,2</sup>. ALKBH7, a mammalian AlkB homologue, localizes in mitochondria and affects metabolism<sup>3</sup>, but its function and mechanism of action are unknown. Here we report an approach to site-specifically detect N<sup>1</sup>-methyladenosine (m<sup>1</sup>A), N<sup>3</sup>-methylcytidine (m<sup>3</sup>C), N<sup>1</sup>-methylguanosine (m<sup>1</sup>G) and N<sup>2</sup>,N<sup>2</sup>-dimethylguanosine (m<sub>2</sub><sup>2</sup>G) modifications simultaneously within all cellular RNAs, and discovered that human ALKBH7 demethylates m<sub>2</sub><sup>2</sup>G and m<sup>1</sup>A within mitochondrial Ile and Leu1 pre-tRNA regions, respectively, in nascent polycistronic mitochondrial RNA<sup>4-6</sup>. 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.