NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis

Xiaofan Jia; Teng Zhang; Chenxi Yang; Kaiyang Liu; Li Wu; Longfei Diao; Yuting Yang; Jie Wu; Yeyi Li; Weiyan Sun; Kai Zhang; Yuhui Jiang; Yuzheng Zhao; Xu Zhang; Peng Jiang; Yideng Jiang; Qiujing Yu; Song Xiang; Yuan Fu; Ting Wang

doi:10.1016/j.cell.2026.01.033

NAD⁺ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis

Cell. 2026 Mar 9:S0092-8674(26)00161-3. doi: 10.1016/j.cell.2026.01.033. Online ahead of print.

Authors

Xiaofan Jia¹, Teng Zhang², Chenxi Yang², Kaiyang Liu³, Li Wu², Longfei Diao², Yuting Yang², Jie Wu², Yeyi Li², Weiyan Sun⁴, Kai Zhang⁵, Yuhui Jiang⁶, Yuzheng Zhao⁶, Xu Zhang⁷, Peng Jiang⁸, Yideng Jiang⁹, Qiujing Yu¹⁰, Song Xiang¹¹, Yuan Fu¹², Ting Wang¹³

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: yuqiujing@uestc.edu.cn.
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: xiangsong@tmu.edu.cn.
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: fuyuan@tmu.edu.cn.
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: twang1@tmu.edu.cn.

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.