TitleNicotinamide adenine dinucleotide is transported into mammalian mitochondria.
Publication TypeJournal Article
Year of Publication2018
AuthorsDavila, A, Liu, L, Chellappa, K, Redpath, P, Nakamaru-Ogiso, E, Paolella, LM, Zhang, Z, Migaud, ME, Rabinowitz, JD, Baur, JA
Date Published2018 06 12
KeywordsAnimals, Biological Transport, Cell Line, HEK293 Cells, HL-60 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mitochondria, Liver, Mitochondria, Muscle, Myoblasts, NAD, Niacinamide, Nicotinamide Mononucleotide

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.

Alternate JournalElife
PubMed ID29893687
PubMed Central IDPMC6013257
Grant ListR01AG043483 / AG / NIA NIH HHS / United States
R01 DK098656 / DK / NIDDK NIH HHS / United States
K12 GM081259 / GM / NIGMS NIH HHS / United States
K12DGM081259 / GM / NIGMS NIH HHS / United States
R01DK098656 / DK / NIDDK NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
R01 AG043483 / AG / NIA NIH HHS / United States