RNA修飾代謝による生体防御機構を解明 ～有害な修飾ヌクレオシドから体を守る仕組み～

2025-08-21 東北大学

<関連情報>

• https://www.tohoku.ac.jp/japanese/2025/08/press20250821-02-RNA.html
• https://www.tohoku.ac.jp/japanese/newimg/pressimg/tohokuuniv-press20250821_02web_RNA.pdf
• https://www.cell.com/cell/fulltext/S0092-8674(25)00863-3

アデノシンキナーゼとADALは、代謝を保護するために修飾されたアデノシンの解毒を協調して行う Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism

Akiko Ogawa ∙ Satoshi Watanabe ∙ Iuliia Ozerova ∙ … ∙ Shinichiro Sawa ∙ Kenji Inaba ∙ Fan-Yan Wei
Cell  Published:August 20, 2025
DOI:https://doi.org/10.1016/j.cell.2025.07.041

Highlights

• m⁶A, m^6,6A, and i⁶A are toxic nucleosides metabolized by ADK and ADAL into IMP
• ADK deficiency drives lethal accumulation of m⁶A, m^6,6A, and i⁶A in mice
• m⁶AMP, m^6,6AMP, and i⁶AMP buildup by ADAL inhibits AMPK, impairing glucose tolerance
• Modified adenosines disrupt lysosomes, linking toxicity with lipid dysregulation

Summary

RNA contains diverse post-transcriptional modifications, and its catabolic breakdown yields numerous modified nucleosides requiring correct processing, but the mechanisms remain unknown. Here, we demonstrate that three RNA-derived modified adenosines, N⁶-methyladenosine (m⁶A), N⁶,N⁶-dimethyladenosine (m^6,6A), and N⁶-isopentenyladenosine (i⁶A), are sequentially metabolized into inosine monophosphate (IMP) to mitigate their intrinsic cytotoxicity. After phosphorylation by adenosine kinase (ADK), they undergo deamination by adenosine deaminase-like (ADAL). In Adal knockout mice, N⁶-modified adenosine monophosphates (AMPs) accumulate and allosterically inhibit AMP-activated protein kinase (AMPK), dysregulating glucose metabolism. Furthermore, ADK deficiency, linked to human inherited disorders of purine metabolism, elevates levels of the three modified adenosines, resulting in early lethality in mice. Mechanistically, excessive m⁶A, m^6,6A, and i⁶A impair lysosomal function by interfering with lysosomal membrane proteins, thereby disrupting lipid metabolism and causing cellular toxicity. Through this nucleotide metabolism pathway and mechanism, cells detoxify modified adenosines, linking modified RNA metabolism to human disease.