2. Academic Validation
  3. NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis

NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis

  • Cell. 2026 Apr 30;189(9):2633-2647.e24. doi: 10.1016/j.cell.2026.01.033.
Xiaofan Jia 1,  Teng Zhang 2,  Chenxi Yang 2,  Kaiyang Liu 3,  Li Wu 2,  Longfei Diao 2,  Yuting Yang 2,  Jie Wu 2,  Yeyi Li 2,  Weiyan Sun 4,  Kai Zhang 5,  Yuhui Jiang 6,  Yuzheng Zhao 6,  Xu Zhang 7,  Peng Jiang 8,  Yideng Jiang 9,  Qiujing Yu 10,  Song Xiang 11,  Yuan Fu 12,  Ting Wang 13
Affiliations

Affiliations

  • 1 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Cancer Institute and Hospital, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China; The Sichuan Provincial Key Laboratory for Genetic Diseases, Institute for Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
  • 2 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Cancer Institute and Hospital, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
  • 3 Department of Biochemistry and Molecular Biology, Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
  • 4 Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Center for Cardiovascular Diseases, Research Center of Basic Medical Sciences, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
  • 5 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 6 Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • 7 Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 8 State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 9 NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China.
  • 10 Key Laboratory of Health Management Medicine, Sichuan Provincial Health Commission, Translational Clinical Immunology Key Laboratory of Sichuan Province, Department of Health Management Center, Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. Electronic address: [email protected].
  • 11 Department of Biochemistry and Molecular Biology, Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China. Electronic address: [email protected].
  • 12 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Cancer Institute and Hospital, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China. Electronic address: [email protected].
  • 13 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Cancer Institute and Hospital, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China; The Sichuan Provincial Key Laboratory for Genetic Diseases, Institute for Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. Electronic address: [email protected].
PMID: 41806834 DOI: 10.1016/j.cell.2026.01.033
Abstract

The regulation of nicotinamide adenine dinucleotide (NAD+) is crucial for numerous life processes. However, the mechanisms leading to NAD+ degradation in mitochondria remain insufficiently defined. Through in silico screening of potential NAD-binding proteins, we discovered a mitochondrial reaction in which NAD+ is hydrolyzed to nicotinamide mononucleotide (NMN) and AMP by SELENOO (SelO), using Mn2+ as cofactor. Catalysis depends on SelO's selenocysteine-serine-serine (CSS) C-terminal residues, particularly the selenocysteine 667. In addition to broad metabolic effects, this reaction plays a pronounced role in lipid utilization via SelO directly associating with fatty acid oxidation (FAO) Enzymes, and it is conserved in both mammalian cells and bacteria. This reaction is responsive to elevated matrix pH, a signal of enhanced mitochondrial respiration, and protects mitochondria from sustained metabolic overactivation. These findings reveal a conserved mechanism for spatiotemporal NAD+ regulation and highlight its physiological significance in both prokaryotes and eukaryotes.

Keywords

NAD; fatty acid oxidation; hydrolysis reaction; mitochondrial homeostasis; nicotinamide adenine dinucleotide; selenocysteine.

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