A sequential, RNA-derived, modified adenosine pathway safeguards cellular metabolism

RNA contains diverse post-transcriptional modifications and its catabolic breakdown yields numerous modified nucleosides that must be properly processed, but the molecular mechanism is largely unknown. Here, we show that three RNA-derived modified adenosines, N6-methyladenosine (m6A), N6,N6-dimethyladenosine (m6,6A), and N6-isopentenyladenosine (i6A), are sequentially metabolized to inosine monophosphate (IMP) to prevent their intrinsic cytotoxicity. These modified adenosines are phosphorylated by adenosine kinase (ADK) followed by adenosine deaminase-like (ADAL)-mediated deamination in both plants and animals. ADAL knockout mice accumulate N6-modified AMPs that allosterically inhibit AMP-activated protein kinase (AMPK), leading to dysregulation of glucose metabolism. Furthermore, ADK deficiency, reported in patients with severe metabolic defects, induces aberrant elevation of m6A/m6,6A/i6A, disrupting lipid metabolism and causing early death in mouse models. The findings unveil a fundamental mechanism by which cells alleviate the toxicity of modified adenosines, and that connects modified adenosines to human disease. In briefRNA catabolism yields diverse nucleosides with modifications attached. Three RNA-derived modified adenosines (m6A, m6,6A, and i6A) are intrinsically toxic and subjected to sequential metabolism to yield inosine monophosphate. Dysregulation of this pathway impairs energy balance and contributes to metabolic diseases. HighlightsO_LICytotoxic RNA catabolism-derived modified adenosines undergo sequential metabolism C_LIO_LIm6A, m6,6A, and i6A are phosphorylated by ADK then deaminated by ADAL to IMP C_LIO_LIm6AMP, m6,6AMP, and i6AMP allosterically inhibit AMP-mediated AMPK activation C_LIO_LILoss of ADK causes the accumulation of m6A, m6,6A, and i6A, and abnormal lipid metabolism, which can lead to genetic disease C_LI