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Research ArticleArticle

Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair, and Apoptosis

Maria Pittelli, Roberta Felici, Vanessa Pitozzi, Lisa Giovannelli, Elisabetta Bigagli, Francesca Cialdai, Giovanni Romano, Flavio Moroni and Alberto Chiarugi
Molecular Pharmacology December 2011, 80 (6) 1136-1146; DOI: https://doi.org/10.1124/mol.111.073916
Maria Pittelli
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Roberta Felici
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Vanessa Pitozzi
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Lisa Giovannelli
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Elisabetta Bigagli
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Francesca Cialdai
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Giovanni Romano
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Flavio Moroni
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Alberto Chiarugi
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Abstract

During the last several years, evidence that various enzymes hydrolyze NAD into bioactive products prompted scientists to revisit or design strategies able to increase intracellular availability of the dinucleotide. However, plasma membrane permeability to NAD and the mitochondrial origin of the dinucleotide still wait to be clearly defined. Here, we report that intracellular NAD contents increased upon exposure of cell lines or primary cultures to exogenous NAD (eNAD). NAD precursors could not reproduce the effects of eNAD, and they were not found in the incubating medium containing eNAD, thereby suggesting direct cellular eNAD uptake. We found that in mitochondria of cells exposed to eNAD, NAD and NADH as well as oxygen consumption and ATP production were increased. Conversely, DNA repair, a well known NAD-dependent process, was unaltered upon eNAD exposure. We also report that eNAD conferred significant cytoprotection from apoptosis triggered by staurosporine, C2-ceramide, or N-methyl-N′-nitro-N-nitrosoguanidine. In particular, eNAD reduced staurosporine-induced loss of mitochondrial membrane potential and ensuing caspase activation. Of importance, pharmacological inhibition or silencing of the NAD-dependent enzyme SIRT1 abrogated the ability of eNAD to provide protection from staurosporine, having no effect on eNAD-dependent protection from C2-ceramide or N-methyl-N′-nitro-N-nitrosoguanidine. Taken together, our findings, on the one hand, strengthen the hypothesis that eNAD crosses the plasma membrane intact and, on the other hand, provide evidence that increased NAD contents significantly affects mitochondrial bioenergetics and sensitivity to apoptosis.

Footnotes

  • This study was supported by the Federazione Italiana Sclerosi Multipla, Regione Toscana (Progetto Salute 2009) and Ente Cassa di Risparmio di Firenze.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.073916.

  • ABBREVIATIONS:

    PARP-1
    poly(ADP-ribose) polymerase-1
    eNAD
    exogenous NAD
    ROS
    reactive oxygen species
    DIV
    days in vitro
    Nam
    nicotinamide
    NMN
    nicotinamide mononucleotide
    NR
    nicotinamide riboside
    MNNG
    N-methyl-N′-nitro-N-nitrosoguanidine
    STP
    staurosporine
    EX-25
    6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
    siRNA
    small interfering RNA
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
    Bicine
    N,N-bis(2-hydroxyethyl)glycine
    PBS
    phosphate-buffered saline
    PBST
    phosphate-buffered saline containing 0.1% Tween 20
    PAR
    poly(ADP-ribose)
    PCR
    polymerase chain reaction
    LC
    liquid chromatography
    iNAD
    intracellular NAD
    FK866
    N-[4-(1-benzoyl-4-piperidinyl)butyl]-3-(3-pyridinyl)-2E-propenamide
    NMNAT
    nicotinamide mononucleotide adenylyltransferase
    MPT
    mitochondrial permeability transition
    PTP
    permeability transition pore.

  • Received June 1, 2011.
  • Accepted September 14, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (6)
Molecular Pharmacology
Vol. 80, Issue 6
1 Dec 2011
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Research ArticleArticle

Exogenous NAD and Cytoprotection

Maria Pittelli, Roberta Felici, Vanessa Pitozzi, Lisa Giovannelli, Elisabetta Bigagli, Francesca Cialdai, Giovanni Romano, Flavio Moroni and Alberto Chiarugi
Molecular Pharmacology December 1, 2011, 80 (6) 1136-1146; DOI: https://doi.org/10.1124/mol.111.073916

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Research ArticleArticle

Exogenous NAD and Cytoprotection

Maria Pittelli, Roberta Felici, Vanessa Pitozzi, Lisa Giovannelli, Elisabetta Bigagli, Francesca Cialdai, Giovanni Romano, Flavio Moroni and Alberto Chiarugi
Molecular Pharmacology December 1, 2011, 80 (6) 1136-1146; DOI: https://doi.org/10.1124/mol.111.073916
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