Nicotinamide adenine dinucleotide is transported into mammalian mitochondria
Open accessAbstract
Mitochondrial NAD levels influence fuel selection, circadian rhythms, and cell survival under stress. It has alternately been argued that NAD in mammalian mitochondria arises from import of cytosolic nicotinamide (NAM), nicotinamide mononucleotide (NMN), or NAD itself. We provide evidence that murine and human mitochondria take up intact NAD. Isolated mitochondria preparations cannot make NAD from NAM, and while NAD is synthesized from NMN, it does not localize to the mitochondrial matrix or effectively support oxidative phosphorylation. Treating cells with nicotinamide riboside that is isotopically labeled on the nicotinamide and ribose moieties results in the appearance of doubly labeled NAD within mitochondria. Analogous experiments with doubly labeled nicotinic acid riboside (labeling cytosolic NAD without labeling NMN) demonstrate that NAD(H) is the imported species. Our results challenge the long-held view that the mitochondrial inner membrane is impermeable to pyridine nucleotides and suggest the existence of an unrecognized mammalian NAD (or NADH) transporter.
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NMN and NAD+/NADH can be transported into mitochondria by unknown systems; NMN is converted to NAD+ by NMNAT3 in the matrix, whereas NR is likely converted to NMN or NAD+ in cytoplasm before transport.
“Recent studies have demonstrated that both NMN and NAD+/NADH can be transported into the mitochondria by unknown systems, and that NMN is converted to NAD+ by NMNAT3 within the mitochondrial matrix, whereas NR is likely converted to NMN or NAD+ in the cytoplasm before transport into mitochondria (Davila et al., 2018; Nikiforov et al., 2011).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Davila et al., 2018
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- Authors
- Davila, A., Liu, L., Chellappa, K., Redpath, P., Nakamaru-Ogiso, E., Paolella, L. M., Zhang, Z., Migaud, M. E., Rabinowitz, J. D., & Baur, J. A.
- Affiliations
- Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
- Princeton University (US)
- University of Pennsylvania (US)
- Queen's University Belfast (GB)
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
- Northeast Agricultural University (CN)
- Corresponding author
- Baur, Joseph A
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-06-12
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6013257
- OpenAlex
- W2808587354
- Cited by
- 142
- References
- 42
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 12 · 2023: 8 · 2022: 17 · 2021: 27 · 2020: 34 · 2019: 21 · 2018: 7
- FWCI
- 12.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098656)
- National Institute on Aging (R01AG043483)
- National Institute of General Medical Sciences (K12DGM081259)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- NAD+, inner mitochondrial membrane permeability, pyridine nucleotides, nicotinamide riboside, NAD biosynthesis, nicotinamide mononucleotide, mitochondrial matrix, oxidative phosphorylation
- MeSH terms
- Animals, Biological Transport, Cell Line, Humans, Male, Mice, Inbred C57BL, Mitochondria, Liver, Mitochondria, Muscle, NAD, Niacinamide, Nicotinamide Mononucleotide, Pyridinium Compounds, HL-60 Cells, Myoblasts, Mice, HEK293 Cells
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