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Slc12a8 is a nicotinamide mononucleotide transporter
Open accessAbstract
Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of NAD+ known to promote cellular NAD+ production and counteract age-associated pathologies associated with a decline in tissue NAD+ levels. How NMN is taken up into cells has not been entirely clear. Here we show that the Slc12a8 gene encodes a specific NMN transporter. We find that Slc12a8 is highly expressed and regulated by NAD+ in the murine small intestine. Slc12a8 knockdown abrogates the uptake of NMN in vitro and in vivo. We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, which is associated with reduced NMN uptake as traced by doubly labeled isotopic NMN. Finally, we observe that Slc12a8 expression is upregulated in the aged murine ileum, which contributes to the maintenance of ileal NAD+ levels. Our work identifies the first NMN transporter and demonstrates that Slc12a8 has a critical role in regulating intestinal NAD+ metabolism.
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“The expression of a transporter in the gut [76] reinforces that NMN could be made bioavailable through oral delivery.”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [76]
In the citing paper
“A newly reported NMN transporter, the Slc12a8, is highly expressed and regulated by NAD+, in the murine small intestine, and Slc12a8 deficiency abrogates the uptake of NMN in vitro and in vivo (Grozio et al., 2019).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Grozio et al., 2019
In the citing paper
“through a transporter called slc12a8, 26-month-old mice (equivalent to 70 human years) that took NMN increased their NAD+ levels to close to 3 months old (equivalent to 12 human months). The content level in young mice increased the cell energy in aged mice [208].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [208]
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“or directly transported by Slc12a8 in the small intestine (Grozio et al., 2019).”
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“The synthesis of these two compounds was described in our previous publication [13] and the cellular transportation might be through the transporters such as Slc12a8 [27].”
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“[67,133] Conversely, the increase in the SCFA-producing microbes like Lactobacillus, Bacteroides , and Akkermansia can improve the downstream effects of NMN through mitochondrial signaling and improved barriers.”
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“SLC12A8 encodes a transporter involved in nicotinamide mononucleotide uptake, a precursor of nicotinamide adenine dinucleotide (NAD + ), 57 which plays an essential role in cellular energy metabolism and redox homeostasis.”
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Physiology and pathophysiology of the NaCl cotransporters in the kidney
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“…of β-NMN could occur directly via a transporter located on the apical side of the intestinal epithelium as intact β-NMN, or indirectly by dephosphorylation into nicotinamide riboside (NR) via the ecto-5 ′ - nucleotidase CD73 (Grozio et al., 2019; Smith and Brenner, 2019; Kim et al., 2023).”
Development of a noncanonical redox cofactor platform in Saccharomyces cerevisiae
Black, W. B., McKee, K., Richardson, K. N., Saleh, S., Gednov, M., Si, A., & Li, H. (2026) · Metabolic Engineering · doi:10.1016/j.ymben.2026.102488
Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells
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Dimerization in the SLC12 family: Structural and biochemical perspectives
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“These precursors use specific transporters (e.g., Slc12a8 of NMN) to accumulate in skeletal muscles, where they stimulate mitochondrial function and oxygen utilization, thereby objectively improving physical performance (15, 16).”
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Lysine Acetylation as a Regulatory Mechanism in Cardiometabolic Disease: A Focus on Sirtuins
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“Slc12a8 has been identified as an NMN transporter to facilitate NMN uptake [181,182].”
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Metadata
- Authors
- Grozio, A., Mills, K. F., Yoshino, J., Bruzzone, S., Sociali, G., Tokizane, K., Lei, H. C., Cunningham, R., Sasaki, Y., Migaud, M. E., & Imai, S.-I.
- Affiliations
- Washington University in St. Louis (US)
- University of Genoa (IT)
- USA Mitchell Cancer Institute (US)
- Corresponding author
- Imai, Shin-ichiro
- ORCID
- Venue
- Nature Metabolism
- Published
- 2019-01-07
- Volume
- 1
- Issue
- 1
- Pages
- 47-57
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6530925
- OpenAlex
- W2903854778
- Cited by
- 287
- References
- 48
- Citations by year
- 2026: 33 · 2025: 37 · 2024: 41 · 2023: 48 · 2022: 39 · 2021: 33 · 2020: 31 · 2019: 22
- FWCI
- 12.04
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- National Institutes of Health (1c06rr015502-01, UL1TR002345)
- Biotechnology and Biological Sciences Research Council (BB/N001842/1)
- National Institute on Aging (R01AG024150, R01AG037457, R01AG047902)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341, P30DK020579)
- National Center for Research Resources (C06-RR-015502)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- NAD+ metabolism, small intestine, sodium-dependent transport, aging, nicotinamide riboside, NAD biosynthesis
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