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Nicotinamide adenine dinucleotide is transported into mammalian mitochondria

  1. Antonio Davila
  2. Ling Liu
  3. Karthikeyani Chellappa
  4. Philip Redpath
  5. Eiko Nakamaru-Ogiso
  6. Lauren M Paolella
  7. Zhigang Zhang
  8. Marie E Migaud
  9. Joshua D Rabinowitz
  10. Joseph A Baur  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Princeton University, United States
  3. Queen's University Belfast, United Kingdom
  4. Northeast Agricultural University, China
Research Article
  • Cited 24
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Cite this article as: eLife 2018;7:e33246 doi: 10.7554/eLife.33246

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.

Article and author information

Author details

  1. Antonio Davila

    Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ling Liu

    Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Karthikeyani Chellappa

    Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Philip Redpath

    School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Eiko Nakamaru-Ogiso

    Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0931-1940
  6. Lauren M Paolella

    Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhigang Zhang

    College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Marie E Migaud

    School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Joshua D Rabinowitz

    Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Joseph A Baur

    Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    baur@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8262-6549

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098656)

  • Joseph A Baur

National Institute on Aging (R01AG043483)

  • Joseph A Baur

National Institute of General Medical Sciences (K12DGM081259)

  • Antonio Davila

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. No live animal work was performed, and animals that were sacrificed for mitochondrial isolation were euthanized according to protocols approved by the institutional animal care and use committee (IACUC) of the University of Pennsylvania (protocol # 804892).

Reviewing Editor

  1. Andrew Dillin, Howard Hughes Medical Institute, University of California, Berkeley, United States

Publication history

  1. Received: October 31, 2017
  2. Accepted: June 10, 2018
  3. Accepted Manuscript published: June 12, 2018 (version 1)
  4. Version of Record published: June 21, 2018 (version 2)
  5. Version of Record updated: July 5, 2018 (version 3)

Copyright

© 2018, Davila et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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