SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters

• Published in: Nature communications 2025-01, Vol.16 (1), p.1181-17, Article 1181
• Main Authors: Chen, Mingyang, Yuan, Luexiang, Chen, Binxin, Chang, Hui, Luo, Jun, Zhang, Hengbin, Chen, Zhongjian, Kong, Jiao, Yi, Yaodong, Bai, Mengru, Dong, Minlei, Zhou, Hui, Jiang, Huidi
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 14/19; 140/58; 38/77; 631/80/509; 631/80/642/333/1465; 631/92/1643; 631/92/577; Biological Transport; Cell Membrane - metabolism; Cell membranes; Cell Respiration; Cellular manufacture; Cellular Senescence; Coding; Equilibrative Nucleoside Transporter 1 - genetics; Equilibrative Nucleoside Transporter 1 - metabolism; Equilibrative-Nucleoside Transporter 2 - genetics; Equilibrative-Nucleoside Transporter 2 - metabolism; HEK293 Cells; Homeostasis; Humanities and Social Sciences; Humans; Metabolites; Mitochondria - metabolism; multidisciplinary; NAD; NAD - metabolism; Niacinamide - metabolism; Niacinamide - pharmacology; Nicotinamide; Nicotinamide Mononucleotide - metabolism; Nicotinic acid; Nucleoside transporter; Nucleosides; Precursors; Respiration; Science; Science (multidisciplinary); Senescence
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-56402-y

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. Nicotinamide is an NAD+ precursor with crucial roles in cellular respiration and energy production. Here, the authors show that equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), encoded by the genes SLC29A1 and SLC29A2 , function in nicotinamide uptake into cells.