SLC25A51 is a Mammalian Mitochondrial NAD Transporter

Overview

Journal Nature

Specialty Science

Date 2020 Sep 9

PMID 32906142

Citations 128

Authors

Timothy S Luongo

Jared M Eller

Mu-Jie Lu

Marc Niere

Fabio Raith

Caroline Perry

Marc R Bornstein

Paul Oliphint

Lin Wang

Melanie R McReynolds

Marie E Migaud

Joshua D Rabinowitz

F Brad Johnson

Kai Johnsson

Mathias Ziegler

Xiaolu A Cambronne

Joseph A Baur

Affiliations

Soon will be listed here.

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 plants, but their existence in mammals remains controversial. Here we demonstrate that mammalian mitochondria can take up intact NAD, and identify SLC25A51 (also known as MCART1)-an essential 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.

Citing Articles

Mitochondrial genetics, signalling and stress responses.

Liu Y, Sulc J, Auwerx J Nat Cell Biol. 2025; 27(3):393-407.

PMID: 40065146 DOI: 10.1038/s41556-025-01625-w.

β-Nicotinamide mononucleotide blocks UVB-induced collagen reduction via regulation of ROS/MAPK/AP-1 and stimulation of mitochondrial proline biosynthesis.

Zhang Y, Ai C, Huang F, Zhao J, Ling Y, Chen W Photochem Photobiol Sci. 2025; 24(2):293-306.

PMID: 40025354 DOI: 10.1007/s43630-025-00692-0.

GEMCAT-a new algorithm for gene expression-based prediction of metabolic alterations.

Sharma S, Sauter R, Hotze M, Prowatke A, Niere M, Kipura T NAR Genom Bioinform. 2025; 7(1):lqaf003.

PMID: 39897103 PMC: 11783570. DOI: 10.1093/nargab/lqaf003.

SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.

Chen M, Yuan L, Chen B, Chang H, Luo J, Zhang H Nat Commun. 2025; 16(1):1181.

PMID: 39885119 PMC: 11782521. DOI: 10.1038/s41467-025-56402-y.

NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.

Ishima T, Kimura N, Kobayashi M, Watanabe C, Jimbo E, Kobayashi R Biomolecules. 2025; 15(1).

PMID: 39858433 PMC: 11764390. DOI: 10.3390/biom15010038.

References

Palmieri F, Rieder B, Ventrella A, Blanco E, Do P, Nunes-Nesi A . Molecular identification and functional characterization of Arabidopsis thaliana mitochondrial and chloroplastic NAD+ carrier proteins. J Biol Chem. 2009; 284(45):31249-59. PMC: 2781523. DOI: 10.1074/jbc.M109.041830. View

Todisco S, Agrimi G, Castegna A, Palmieri F . Identification of the mitochondrial NAD+ transporter in Saccharomyces cerevisiae. J Biol Chem. 2005; 281(3):1524-31. DOI: 10.1074/jbc.M510425200. View

Berger F, Ramirez-Hernandez M, Ziegler M . The new life of a centenarian: signalling functions of NAD(P). Trends Biochem Sci. 2004; 29(3):111-8. DOI: 10.1016/j.tibs.2004.01.007. View

Yang H, Yang T, Baur J, Perez E, Matsui T, Carmona J . Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 2007; 130(6):1095-107. PMC: 3366687. DOI: 10.1016/j.cell.2007.07.035. View

VanLinden M, Dolle C, Pettersen I, Kulikova V, Niere M, Agrimi G . Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the Metabolic Profile of Human Cells. J Biol Chem. 2015; 290(46):27644-59. PMC: 4646015. DOI: 10.1074/jbc.M115.654129. View

Wang T, Birsoy K, Hughes N, Krupczak K, Post Y, Wei J . Identification and characterization of essential genes in the human genome. Science. 2015; 350(6264):1096-101. PMC: 4662922. DOI: 10.1126/science.aac7041. View

Bertomeu T, Coulombe-Huntington J, Chatr-Aryamontri A, Bourdages K, Coyaud E, Raught B . A High-Resolution Genome-Wide CRISPR/Cas9 Viability Screen Reveals Structural Features and Contextual Diversity of the Human Cell-Essential Proteome. Mol Cell Biol. 2017; 38(1). PMC: 5730719. DOI: 10.1128/MCB.00302-17. View

Yoshino J, Baur J, Imai S . NAD Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2017; 27(3):513-528. PMC: 5842119. DOI: 10.1016/j.cmet.2017.11.002. View

Cambronne X, Stewart M, Kim D, Jones-Brunette A, Morgan R, Farrens D . Biosensor reveals multiple sources for mitochondrial NAD⁺. Science. 2016; 352(6292):1474-7. PMC: 6530784. DOI: 10.1126/science.aad5168. View

10.

Pittelli M, Formentini L, Faraco G, Lapucci A, Rapizzi E, Cialdai F . Inhibition of nicotinamide phosphoribosyltransferase: cellular bioenergetics reveals a mitochondrial insensitive NAD pool. J Biol Chem. 2010; 285(44):34106-14. PMC: 2962509. DOI: 10.1074/jbc.M110.136739. View

11.

Sims C, Guan Y, Mukherjee S, Singh K, Botolin P, Davila Jr A . Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock. JCI Insight. 2018; 3(17). PMC: 6171817. DOI: 10.1172/jci.insight.120182. View

12.

Titus S, Moran R . Retrovirally mediated complementation of the glyB phenotype. Cloning of a human gene encoding the carrier for entry of folates into mitochondria. J Biol Chem. 2000; 275(47):36811-7. DOI: 10.1074/jbc.M005163200. View

13.

Spaan A, Ijlst L, van Roermund C, Wijburg F, Wanders R, Waterham H . Identification of the human mitochondrial FAD transporter and its potential role in multiple acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2005; 86(4):441-7. DOI: 10.1016/j.ymgme.2005.07.014. View

14.

Berger F, Lau C, Dahlmann M, Ziegler M . Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem. 2005; 280(43):36334-41. DOI: 10.1074/jbc.M508660200. View

15.

Davila A, Liu L, Chellappa K, Redpath P, Nakamaru-Ogiso E, Paolella L . Nicotinamide adenine dinucleotide is transported into mammalian mitochondria. Elife. 2018; 7. PMC: 6013257. DOI: 10.7554/eLife.33246. View

16.

Fletcher R, Ratajczak J, Doig C, Oakey L, Callingham R, Da Silva Xavier G . Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol Metab. 2017; 6(8):819-832. PMC: 5518663. DOI: 10.1016/j.molmet.2017.05.011. View

17.

Nikiforov A, Dolle C, Niere M, Ziegler M . Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. J Biol Chem. 2011; 286(24):21767-78. PMC: 3122232. DOI: 10.1074/jbc.M110.213298. View

18.

Hikosaka K, Ikutani M, Shito M, Kazuma K, Gulshan M, Nagai Y . Deficiency of nicotinamide mononucleotide adenylyltransferase 3 (nmnat3) causes hemolytic anemia by altering the glycolytic flow in mature erythrocytes. J Biol Chem. 2014; 289(21):14796-811. PMC: 4031534. DOI: 10.1074/jbc.M114.554378. View

19.

Yamamoto M, Hikosaka K, Mahmood A, Tobe K, Shojaku H, Inohara H . Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo. PLoS One. 2016; 11(1):e0147037. PMC: 4710499. DOI: 10.1371/journal.pone.0147037. View

20.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View