IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56402-y.html
   My bibliography  Save this article

SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters

Author

Listed:
  • Mingyang Chen

    (Zhejiang University
    Jinhua Institute of Zhejiang University)

  • Luexiang Yuan

    (Zhejiang University)

  • Binxin Chen

    (Zhejiang University
    Westlake University)

  • Hui Chang

    (Zhejiang University)

  • Jun Luo

    (Zhejiang University
    Westlake University)

  • Hengbin Zhang

    (Zhejiang University)

  • Zhongjian Chen

    (Chinese Academy of Sciences)

  • Jiao Kong

    (Zhejiang University)

  • Yaodong Yi

    (Zhejiang University)

  • Mengru Bai

    (Westlake University)

  • Minlei Dong

    (Zhejiang University)

  • Hui Zhou

    (Zhejiang University
    Jinhua Institute of Zhejiang University)

  • Huidi Jiang

    (Zhejiang University
    Jinhua Institute of Zhejiang University)

Abstract

Nicotinamide (NAM), a main precursor of NAD+, is essential for cellular fuel respiration, energy production, and other cellular processes. Transporters for other precursors of NAD+ such as nicotinic acid and nicotinamide mononucleotide (NMN) have been identified, but the cellular transporter of nicotinamide has not been elucidated. Here, we demonstrate that equilibrative nucleoside transporter 1 and 2 (ENT1 and 2, encoded by SLC29A1 and 2) drive cellular nicotinamide uptake and establish nicotinamide metabolism homeostasis. In addition, ENT1/2 exhibits a strong capacity to change the cellular metabolite composition and the transcript, especially those related to nicotinamide. We further observe that ENT1/2 regulates cellular respiration and senescence, contributing by altering the NAD+ pool level and mitochondrial status. Changes to cellular respiration, mitochondrial status and senescence by ENT1/2 knockdown are reversed by NMN supplementation. Together, ENT1 and ENT2 act as both cellular nicotinamide-level keepers and nicotinamide biological regulators through their NAM transport functions.

Suggested Citation

  • Mingyang Chen & Luexiang Yuan & Binxin Chen & Hui Chang & Jun Luo & Hengbin Zhang & Zhongjian Chen & Jiao Kong & Yaodong Yi & Mengru Bai & Minlei Dong & Hui Zhou & Huidi Jiang, 2025. "SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56402-y
    DOI: 10.1038/s41467-025-56402-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56402-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-56402-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    2. Timothy S. Luongo & Jared M. Eller & Mu-Jie Lu & Marc Niere & Fabio Raith & Caroline Perry & Marc R. Bornstein & Paul Oliphint & Lin Wang & Melanie R. McReynolds & Marie E. Migaud & Joshua D. Rabinowi, 2020. "SLC25A51 is a mammalian mitochondrial NAD+ transporter," Nature, Nature, vol. 588(7836), pages 174-179, December.
    3. A. Phillip West & William Khoury-Hanold & Matthew Staron & Michal C. Tal & Cristiana M. Pineda & Sabine M. Lang & Megan Bestwick & Brett A. Duguay & Nuno Raimundo & Donna A. MacDuff & Susan M. Kaech &, 2015. "Mitochondrial DNA stress primes the antiviral innate immune response," Nature, Nature, vol. 520(7548), pages 553-557, April.
    4. Mei T. Tran & Zsuzsanna K. Zsengeller & Anders H. Berg & Eliyahu V. Khankin & Manoj K. Bhasin & Wondong Kim & Clary B. Clish & Isaac E. Stillman & S. Ananth Karumanchi & Eugene P. Rhee & Samir M. Pari, 2016. "PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection," Nature, Nature, vol. 531(7595), pages 528-532, March.
    5. Xuan Sun & Benjamin Cao & Marina Naval-Sanchez & Tony Pham & Yu Bo Yang Sun & Brenda Williams & Shen Y. Heazlewood & Nikita Deshpande & Jinhua Li & Felix Kraus & James Rae & Quan Nguyen & Hamed Yari &, 2021. "Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    6. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    7. Liang Yang & Junfeng Shen & Chunhua Liu & Zhonghua Kuang & Yong Tang & Zhengjiang Qian & Min Guan & Yongfeng Yang & Yang Zhan & Nan Li & Xiang Li, 2023. "Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    9. Joanna Ratajczak & Magali Joffraud & Samuel A. J. Trammell & Rosa Ras & Núria Canela & Marie Boutant & Sameer S. Kulkarni & Marcelo Rodrigues & Philip Redpath & Marie E. Migaud & Johan Auwerx & Oscar , 2016. "NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    10. Eladio J. Márquez & Cheng-han Chung & Radu Marches & Robert J. Rossi & Djamel Nehar-Belaid & Alper Eroglu & David J. Mellert & George A. Kuchel & Jacques Banchereau & Duygu Ucar, 2020. "Sexual-dimorphism in human immune system aging," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ahrum Son & Hyunsoo Kim & Jolene K. Diedrich & Casimir Bamberger & Daniel B. McClatchy & Stuart A. Lipton & John R. Yates, 2024. "Using in vivo intact structure for system-wide quantitative analysis of changes in proteins," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Julia Kornienko & Marta Rodríguez-Martínez & Kai Fenzl & Florian Hinze & Daniel Schraivogel & Markus Grosch & Brigit Tunaj & Dominik Lindenhofer & Laura Schraft & Moritz Kueblbeck & Eric Smith & Chad , 2023. "Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Di Tang & Hamed Khakzad & Elisabeth Hjortswang & Lars Malmström & Simon Ekström & Lotta Happonen & Johan Malmström, 2024. "Streptolysin O accelerates the conversion of plasminogen to plasmin," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Tian-Yi Zhang & Yao-Qi Chen & Jing-Cong Tan & Jin-An Zhou & Wan-Ning Chen & Tong Jiang & Jin-Yin Zha & Xiang-Kang Zeng & Bo-Wen Li & Lu-Qi Wei & Yun Zou & Lu-Yao Zhang & Yue-Mei Hong & Xiu-Li Wang & R, 2024. "Global fungal-host interactome mapping identifies host targets of candidalysin," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative Artificial Intelligence," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, pages 7-46, National Bureau of Economic Research, Inc.
    6. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    8. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Zhao-Shan Chen & Hsiang-Chi Huang & Xiangkun Wang & Karin Schön & Yane Jia & Michael Lebens & Danica F. Besavilla & Janarthan R. Murti & Yanhong Ji & Aishe A. Sarshad & Guohua Deng & Qiyun Zhu & David, 2025. "Influenza A Virus H7 nanobody recognizes a conserved immunodominant epitope on hemagglutinin head and confers heterosubtypic protection," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    10. Sourav Nayak & Thomas J. Peto & Michal Kucharski & Rupam Tripura & James J. Callery & Duong Tien Quang Huy & Mathieu Gendrot & Dysoley Lek & Ho Dang Trung Nghia & Rob W. Pluijm & Nguyen Dong & Le Than, 2024. "Population genomics and transcriptomics of Plasmodium falciparum in Cambodia and Vietnam uncover key components of the artemisinin resistance genetic background," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    13. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    14. Katherine A. Ray & Joshua D. Lutgens & Ramesh Bista & Jie Zhang & Ronak R. Desai & Melissa Hirsch & Takeshi Miyazawa & Antonio Cordova & Adrian T. Keatinge-Clay, 2024. "Assessing and harnessing updated polyketide synthase modules through combinatorial engineering," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    15. Fan Lu & Liang Zhu & Thomas Bromberger & Jun Yang & Qiannan Yang & Jianmin Liu & Edward F. Plow & Markus Moser & Jun Qin, 2022. "Mechanism of integrin activation by talin and its cooperation with kindlin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    16. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    17. Yudong Gao & Daichi Shonai & Matthew Trn & Jieqing Zhao & Erik J. Soderblom & S. Alexandra Garcia-Moreno & Charles A. Gersbach & William C. Wetsel & Geraldine Dawson & Dmitry Velmeshev & Yong-hui Jian, 2024. "Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    18. Martin F. Peter & Christian Gebhardt & Rebecca Mächtel & Gabriel G. Moya Muñoz & Janin Glaenzer & Alessandra Narducci & Gavin H. Thomas & Thorben Cordes & Gregor Hagelueken, 2022. "Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    19. Morié Ishida & Adriana E. Golding & Tal Keren-Kaplan & Yan Li & Tamas Balla & Juan S. Bonifacino, 2024. "ARMH3 is an ARL5 effector that promotes PI4KB-catalyzed PI4P synthesis at the trans-Golgi network," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    20. Jutta Diessl & Jens Berndtsson & Filomena Broeskamp & Lukas Habernig & Verena Kohler & Carmela Vazquez-Calvo & Arpita Nandy & Carlotta Peselj & Sofia Drobysheva & Ludovic Pelosi & F.-Nora Vögtle & Fab, 2022. "Manganese-driven CoQ deficiency," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56402-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.