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Elife. 2018 Jun 12;7. pii: e33246. doi: 10.7554/eLife.33246.

Nicotinamide adenine dinucleotide is transported into mammalian mitochondria.

Author information

1
Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
2
PARC, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
3
Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, United States.
4
School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
5
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
6
College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
7
Mitchell Cancer Institute, University of South Alabama, Mobile, United States.
#
Contributed equally

Abstract

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.

KEYWORDS:

NAD; NADH; cell biology; mitochondria; mononucleotide; mouse; niacin; nicotinamide

PMID:
29893687
PMCID:
PMC6013257
DOI:
10.7554/eLife.33246
[Indexed for MEDLINE]
Free PMC Article

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