Nicotinamide adenine dinucleotide is transported into mammalian mitochondria

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.

• Publication year

  2018

• Venue

  eLife

• Publication date

  2018-06-12

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.7554/eLife.33246PMID 29893687PMCID 6013257
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Mouse Nudt13 is a Mitochondrial Nudix Hydrolase with NAD(P)H Pyrophosphohydrolase Activity

  2017influential reference
• Mitochondrial NUDIX hydrolases: A metabolic link between NAD catabolism, GTP and mitochondrial dynamics

  2017cited by this paper
• Metabolite Spectral Accuracy on Orbitraps.

  2017cited by this paper
• Biosensor reveals multiple sources for mitochondrial NAD+

  2016cited by this paper
• NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

  2016cited by this paper
• Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle.

  2016cited by this paper
• Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo

  2016cited by this paper
• Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the Metabolic Profile of Human Cells*

  2015cited by this paper
• MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins

  2015cited by this paper
• Deficiency of Nicotinamide Mononucleotide Adenylyltransferase 3 (Nmnat3) Causes Hemolytic Anemia by Altering the Glycolytic Flow in Mature Erythrocytes*

  2014cited by this paper
• The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters*

  2014cited by this paper
• NAD and ADP‐ribose metabolism in mitochondria

  2013cited by this paper
• Circadian Clock NAD+ Cycle Drives Mitochondrial Oxidative Metabolism in Mice

  2013cited by this paper
• The mitochondrial transporter family SLC25: identification, properties and physiopathology.

  2013influential reference
• Insight into Molecular and Functional Properties of NMNAT3 Reveals New Hints of NAD Homeostasis within Human Mitochondria

  2013cited by this paper
• The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A, FAD and NAD+.

  2012cited by this paper
• The dynamic regulation of NAD metabolism in mitochondria.

  2012cited by this paper
• Regulation of Poly(ADP-ribose) Polymerase-1-dependent Gene Expression through Promoter-directed Recruitment of a Nuclear NAD+ Synthase*

  2012cited by this paper
• Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells

  2011cited by this paper
• Metabolomic analysis via reversed-phase ion-pairing liquid chromatography coupled to a stand alone orbitrap mass spectrometer.

  2010cited by this paper
• Inhibition of Nicotinamide Phosphoribosyltransferase

  2010cited by this paper
• Nicotinamide Mononucleotide Adenylyltransferase Expression in Mitochondrial Matrix Delays Wallerian Degeneration

  2009cited by this paper
• Enzymes in the NAD+ Salvage Pathway Regulate SIRT1 Activity at Target Gene Promoters*

  2009cited by this paper
• Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival.

  2007cited by this paper
• Fourteen novel human members of mitochondrial solute carrier family 25 (SLC25) widely expressed in the central nervous system.

  2006cited by this paper
• Subcellular Compartmentation and Differential Catalytic Properties of the Three Human Nicotinamide Mononucleotide Adenylyltransferase Isoforms*

  2005cited by this paper
• A candidate NAD+ transporter in an intracellular bacterial symbiont related to Chlamydiae

  2004cited by this paper
• The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells*

  2004cited by this paper
• Survival

  2004influential reference
• Identification of the Mitochondrial NAD+ Transporter in Saccharomyces cerevisiae*

  2004cited by this paper
• Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans.

  2004cited by this paper
• Matrix volume measurements challenge the existence of diazoxide/glibencamide‐sensitive KATP channels in rat mitochondria

  2003cited by this paper
• Connexin 43 hemichannels mediate Ca2+‐regulated transmembrane NAD+ fluxes in intact cells

  2001cited by this paper
• Evidence of a role for cyclic ADP‐ribose in calcium signalling and neurotransmitter release in cultured astrocytes

  2001cited by this paper
• Rat liver mitochondria can synthesize nicotinamide adenine dinucleotide from nicotinamide mononucleotide and ATP via a putative matrix nicotinamide mononucleotide adenylyltransferase.

  1996cited by this paper
• Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines.

  1996cited by this paper
• Fluxes of Nicotinamide Adenine Dinucleotides through Mitochondrial Membranes in Human Cultured Cells*

  1996cited by this paper
• Apparent pyridine nucleotide synthesis in mitochondria: an artifact of NMN and NAD glycohydrolase activity?

  1981cited by this paper
• Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle

  1977cited by this paper
• Macromolecular enzymatic product of NAD+ in liver mitochondria.

  1975cited by this paper
• Systems used for the transport of substrates into mitochondria.

  1968cited by this paper
• The respiratory chain and oxidative phosphorylation.

  1956cited by this paper

• Mitochondrial NMNAT3 reduces amyloid aggregates in Drosophila and alters the amyloid processing in the 3xTgAD mouse

  2026cites this paper
• NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations

  2026cites this paper
• Exploring NAD+ Biology in Fish: From Cellular Metabolism to Ecological Adaptations and Aquaculture Strategies

  2025cites this paper
• NAD+ precursor supplementation in human ageing: clinical evidence and challenges

  2025cites this paper
• NAD+ Homeostasis and Autophagy: Integrated Control Through Nutrient Signaling in Yeast and Mammals

  2025cites this paper
• 13C tracing in synaptosomes reveals that SGLT2 inhibition with dapagliflozin prevents metabolic deficits in the 5X-FAD model of Alzheimer’s Disease

  2025cites this paper
• Neuroprotection by Mitochondrial NAD Against Glutamate-Induced Excitotoxicity

  2025cites this paper
• Insights into the gut microbiome-metabolite dynamics in breast cancer

  2025cites this paper
• Mitochondrial NAD+ deficiency in vascular smooth muscle impairs collagen III turnover to trigger thoracic and abdominal aortic aneurysm

  2025influential citation
• Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches

  2024cites this paper
• Inhibiting HSD17B8 suppresses the cell proliferation caused by PTEN failure

  2024cites this paper
• The interplay of NAD and hypoxic stress and its relevance for ageing.

  2024cites this paper
• Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+

  2024cites this paper
• The cellular symphony of redox cofactor management by yeasts in wine fermentation.

  2024cites this paper
• NAD metabolism and heart failure: Mechanisms and therapeutic potentials.

  2024cites this paper
• Exploring nicotinamide adenine dinucleotide precursors across biosynthesis pathways: Unraveling their role in the ovary

  2024cites this paper
• Regulation of and challenges in targeting NAD+ metabolism

  2024cites this paper
• Novel insight into nicotinamide adenine dinucleotide and related metabolites in cancer patients undergoing surgery

  2024cites this paper
• The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity

  2024cites this paper
• Formulation and characterization of pH-responsive pickering emulsions stabilized by soy protein isolate/nicotinamide mononucleotide complexes for controlled drug release

  2023cites this paper
• Aging of stallion spermatozoa stored in vitro is delayed at 22°C using a 67 mm glucose–10 mm pyruvate‐based media

  2023cites this paper
• Impact of NAD+ metabolism on ovarian aging

  2023cites this paper
• NAD+ regulates nucleotide metabolism and genomic DNA replication

  2023cites this paper
• Quantitative dynamics of intracellular NMN by genetically encoded biosensor

  2023cites this paper
• Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.

  2023cites this paper
• Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels

  2023cites this paper
• NAD+ Precursors in Human Health and Disease: Current Status and Future Prospects

  2023cites this paper
• The TAS1R2 sweet taste receptor regulates skeletal muscle mass and fitness

  2023cites this paper
• Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

  2022cites this paper
• Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria

  2022cites this paper
• Loss-of-function approach using mouse retinal explants showed pivotal roles of Nmnat2 in early and middle stages of retinal development

  2022cites this paper
• Insights in Biomedicine Role of Cx43 and SLC25A51 Transporters-New Perspectives in NAD + Supplementation to Improve Mitochondrial Performance

  2022cites this paper
• Perinatal exposure to glyphosate-based herbicides impairs progeny health and placental angiogenesis by disturbing mitochondrial function.

  2022cites this paper
• PARP-inhibition reprograms macrophages toward an anti-tumor phenotype

  2022cites this paper
• Understanding the role of NRF2 signalling in cancer.

  2022cites this paper
• Maintenance of small molecule redox homeostasis in mitochondria

  2022cites this paper
• A practical guide for the analysis, standardization and interpretation of oxygen consumption measurements

  2022cites this paper
• The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.

  2022cites this paper
• Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations

  2022cites this paper
• Mitochondria as Cellular and Organismal Signaling Hubs.

  2022cites this paper
• NAD+ and its possible role in gut microbiota: Insights on the mechanisms by which gut microbes influence host metabolism

  2022cites this paper
• MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle.

  2022cites this paper
• Synthesis of Mixed Dinucleotides by Mechanochemistry

  2022cites this paper
• Harnessing NAD+ Metabolism as Therapy for Cardiometabolic Diseases

  2022cites this paper
• Physiological and Pathophysiological Roles of Metabolic Pathways for NET Formation and Other Neutrophil Functions

  2022cites this paper
• Metabolic adaptation to the chronic loss of Ca2+ signaling induced by KO of IP3 receptors or the mitochondrial Ca2+ uniporter

  2021cites this paper
• Mitochondrial NAD+ Controls Nuclear ARTD1-Induced ADP-Ribosylation

  2021cites this paper
• Mitochondrial translation deficiency impairs NAD+‐mediated lysosomal acidification

  2021cites this paper
• Maestro of the SereNADe: SLC25A51 Orchestrates Mitochondrial NAD.

  2021cites this paper
• SIRT4 regulates rat dental papilla cell differentiation by promoting mitochondrial functions.

  2021cites this paper
• SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside

  2021cites this paper
• The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

  2021influential citation
• Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments

  2021cites this paper
• MDH2 is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle

  2021cites this paper
• Protective Effects of Nicotinamide Adenine Dinucleotide and Related Precursors in Alzheimer’s Disease: A Systematic Review of Preclinical Studies

  2021cites this paper
• Evolving concepts in NAD+ metabolism.

  2021cites this paper
• NAD+ and NAFLD – caution, causality and careful optimism

  2021influential citation
• Chronic depletion of subcellular NAD pools reveals their interconnectivity and a buffering function of mitochondria

  2021cites this paper
• Welcome to the Family: Identification of the NAD+ Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25

  2021influential citation
• Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury

  2021cites this paper
• Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells

  2021cites this paper
• NAD+ in Alzheimer’s Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo

  2021cites this paper
• NAD+ Degrading Enzymes, Evidence for Roles During Infection

  2021cites this paper
• The balance between NAD+ biosynthesis and consumption in ageing.

  2021cites this paper
• Plant Mitochondria - Past, present and future.

  2021cites this paper
• Rescuing mitochondria in traumatic brain injury and intracerebral hemorrhages - A potential therapeutic approach.

  2021cites this paper
• NAD+ flux is maintained in aged mice despite lower tissue concentrations.

  2021cites this paper
• Protective effects of vitexin on cadmium-induced renal toxicity in rats

  2021cites this paper
• The assembly, regulation and function of the mitochondrial respiratory chain

  2021cites this paper
• Regulation of NAD+ metabolism in aging and disease.

  2021cites this paper
• Metabolic Fuel for Epigenetic: Nuclear Production Meets Local Consumption

  2021cites this paper
• Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation

  2021cites this paper
• The role of protein acetylation in regulating mitochondrial fusion and fission.

  2021cites this paper
• NAD+ flux is maintained in aged mice

  2020cites this paper
• Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import

  2020cites this paper
• Differential processing and localization of human Nocturnin controls metabolism of mRNA and nicotinamide adenine dinucleotide cofactors

  2020influential citation
• Decoding the Rosetta Stone of Mitonuclear Communication.

  2020cites this paper
• A systematic genetic interaction map of human solute carriers assigns a role to SLC25A51/MCART1 in mitochondrial NAD uptake

  2020cites this paper
• SLC25A51 is a mammalian mitochondrial NAD+ transporter

  2020cites this paper
• Rapamycin maintains NAD+/NADH redox homeostasis in muscle cells

  2020cites this paper
• NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

  2020cites this paper
• Nuclear metabolism and the regulation of the epigenome

  2020cites this paper
• Intimate Relations—Mitochondria and Ageing

  2020cites this paper
• Experimental Neurology

  2020cites this paper
• Warburg-like Metabolic Reprogramming in Aging Intestinal Stem Cells Contributes to Tissue Hyperplasia

  2020cites this paper
• Role of Metabolism in Regulating Immune Cell Fate Decisions

  2020cites this paper
• MCART1 is required for mitochondrial NAD transport

  2020cites this paper
• MCART1/SLC25A51 is required for mitochondrial NAD transport

  2020cites this paper
• Targeting metabolic reprogramming in metastatic melanoma: The key role of nicotinamide phosphoribosyltransferase (NAMPT).

  2020cites this paper
• Minireview Exploring the Biological Cycle of Vitamin B3 and Its Influence on Oxidative Stress: Further Molecular and Clinical Aspects

  2020cites this paper
• Role of NUDIX Hydrolases in NAD and ADP-Ribose Metabolism in Mammals

  2020cites this paper
• NAD+ Metabolism as an Emerging Therapeutic Target for Cardiovascular Diseases Associated With Sudden Cardiac Death

  2020cites this paper
• Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox

  2020cites this paper
• Location, Location, Location: Compartmentalization of NAD+ Synthesis and Functions in Mammalian Cells.

  2020cites this paper
• Nicotinamide adenine dinucleotide (NAD+): essential redox metabolite, co-substrate and an anti-cancer and anti-ageing therapeutic target.

  2020cites this paper
• The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it?

  2020cites this paper
• Mitochondria and chronic effects of cancer therapeutics: The clinical implications

  2020cites this paper
• NAD metabolism in aging and cancer

  2020cites this paper
• Hexavalent chromium induces mitochondrial dynamics disorder in rat liver by inhibiting AMPK/PGC-1α signaling pathway.

  2020cites this paper
• Improving retinal mitochondrial function as a treatment for age-related macular degeneration

  2020cites this paper