SLC25A51 is a mammalian mitochondrial NAD+ transporter

  • Nature. 2020 Dec;588(7836):174-179. doi: 10.1038/s41586-020-2741-7.
Timothy S Luongo  1 ,  Jared M Eller  2 ,  Mu-Jie Lu  2 ,  Marc Niere  3 ,  Fabio Raith  4  5 ,  Caroline Perry  1 ,  Marc R Bornstein  1 ,  Paul Oliphint  2 ,  Lin Wang  6 ,  Melanie R McReynolds  6 ,  Marie E Migaud  7 ,  Joshua D Rabinowitz  6 ,  F Brad Johnson  8 ,  Kai Johnsson  4  9 ,  Mathias Ziegler  3 ,  Xiaolu A Cambronne  10 ,  Joseph A Baur  11
Affiliations
  • 1. Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
  • 3. Department of Biomedicine, University of Bergen, Bergen, Norway.
  • 4. Department of Chemical Biology, Max Planck Institute for Medical Research, Heidelberg, Germany.
  • 5. Faculty of Chemistry and Earth Sciences, University of Heidelberg, Heidelberg, Germany.
  • 6. Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, NJ, USA.
  • 7. Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
  • 8. Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 9. Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • 10. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA. [email protected].
  • 11. Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
PMID: 32906142 DOI: 10.1038/s41586-020-2741-7
Abstract

Mitochondria require nicotinamide adenine dinucleotide (NAD+) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD+ transporters have been identified in yeast and Plants1,2, but their existence in mammals remains controversial3-5. Here we demonstrate that mammalian mitochondria can take up intact NAD+, and identify SLC25A51 (also known as MCART1)-an essential6,7 mitochondrial protein of previously unknown function-as a mammalian mitochondrial NAD+ transporter. Loss of SLC25A51 decreases mitochondrial-but not whole-cell-NAD+ content, impairs mitochondrial respiration, and blocks the uptake of NAD+ into isolated mitochondria. Conversely, overexpression of SLC25A51 or SLC25A52 (a nearly identical paralogue of SLC25A51) increases mitochondrial NAD+ levels and restores NAD+ uptake into yeast mitochondria lacking endogenous NAD+ transporters. Together, these findings identify SLC25A51 as a mammalian transporter capable of importing NAD+ into mitochondria.