2. Academic Validation
  3. Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism

Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism

  • Cell. 2025 Aug 13:S0092-8674(25)00863-3. doi: 10.1016/j.cell.2025.07.041.
Akiko Ogawa 1,  Satoshi Watanabe 2,  Iuliia Ozerova 3,  Allen Yi-Lun Tsai 4,  Yoshihiko Kuchitsu 5,  Harrison Byron Chong 6,  Tomoyoshi Kawakami 7,  Jirio Fuse 7,  Wei Han 8,  Ryuhei Kudo 9,  Tomoki Naito 10,  Kota Sato 11,  Toru Nakazawa 12,  Yasunori Saheki 10,  Akiyoshi Hirayama 9,  Peter F Stadler 13,  Mieko Arisawa 8,  Kimi Araki 14,  Liron Bar-Peled 15,  Tomohiko Taguchi 5,  Shinichiro Sawa 4,  Kenji Inaba 2,  Fan-Yan Wei 16
Affiliations

Affiliations

  • 1 Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai 980-8575, Japan; Department of Modomics Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan. Electronic address: akiko.ogawa.e5@tohoku.ac.jp.
  • 2 Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
  • 3 Bioinformatics Group, Department of Computer Science & Interdisciplinary Center for Bioinformatics, Leipzig University, Härtelstraße 16-18, Leipzig 04107, Germany.
  • 4 International Research Center for Agricultural and Environmental Biology (IRCAEB), Kumamoto University, Kumamoto 860-8555, Japan; Graduate School of Advanced Science and Technology, Kumamoto University, Kumamoto 860-8555, Japan.
  • 5 Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai 980-8577, Japan.
  • 6 Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • 7 Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai 980-8575, Japan; School of Medicine, Tohoku University, Sendai 980-8575, Japan.
  • 8 Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan.
  • 9 Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0035, Yamagata, Japan.
  • 10 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore.
  • 11 Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
  • 12 Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Collaborative Program for Wellbeing Design Institute for Health, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Co-creation Center of Social System for Health and Wellness, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
  • 13 Bioinformatics Group, Department of Computer Science & Interdisciplinary Center for Bioinformatics, Leipzig University, Härtelstraße 16-18, Leipzig 04107, Germany; Max Planck Institute for Mathematics in the Sciences, Inselstraße 22, Leipzig 04103, Germany; Institute for Theoretical Chemistry, University of Vienna, Währinger Straße 17, Vienna 1090, Austria; Center for Non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg 2000, Denmark; Facultad de Ciencias, Universidad Nacional de Colombia, Ciudad Universitaria, Bogotá 111321, Colombia; Santa Fe Institute, 1399 Hyde Park Road, Santa Fe, NM 87501, USA; Zuse School of Embedded and Composite AI (SECAI) Dresden-Leipzig & Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI) Dresden-Leipzig & German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig & Centre for Biotechnology and Biomedicine & LIFE - Leipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig 04103, Germany.
  • 14 Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan; Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto 860-8556, Japan.
  • 15 Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
  • 16 Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai 980-8575, Japan; Department of Modomics Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan. Electronic address: fanyan.wei.d3@tohoku.ac.jp.
PMID: 40840445 DOI: 10.1016/j.cell.2025.07.041
Abstract

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 (m6,6A), 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, m6,6A, 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.

Keywords

ADAL; ADK; AMP-activated protein kinase; AMPK; Adenosine deaminase-like; Adenosine kinase; Lipid metabolism; Lysosome; Modified RNA metabolism; Purine metabolism; RNA modification; m(6)A.

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