NAD metabolism in oncogene-induced senescence and mitochondrial dysfunction-associated senescence (Homo sapiens)

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8, 923, 878777738228775278781, 727774, 6728Growth ArrestPentose PhospatePathwayCYTOPLASMCommon forboth pathwaysCell SenescenceMITOCHONDRIAPromotion ofCancer ProgressionMitochondrial Dysfunction-Associated SenescenceHuRCanonical NF-KB PathwayPARP1PGMSCO2NADIL-10AMPKa1NMNSIRT3MalateSIRT5ADP/ATPGOT2IL8AspartateOAASIRT2GOT1TP53G6PDHCCL27pyruvateMDH1IL1BTranscription factor p65NAMPTp38 MAPKnicotinamidep21GLUT1PRPPNMNAT2SA-B-GalSIRT1MDH2lactateFatty AcidBeta OxidationNADHTNF-aOncogene Induced SenescenceIL6GLUT4GlycolysisHMGA1pRBp16High proinflammatory SASPMalateOAAAspartateMitochondrial Oxidative PhosphorylationTCA Cycle7NAD/NADHOncogene Induced SenescenceMitochondrial Dysfunction-Associated Senescence


The uppermost part of the pathway includes part of the general NAM salvage pathway in the cytosol as it is relevant to senescence-induced changes to NAD metabolism. In this pathway, NAD levels are maintained through recycling back to NAD from nicotinamide (NAM) and nicotinamide mononucleotide (NMN) (Braidy et al., 2019). The conversion from NAM to NMN is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT), while the conversion from NMN to NAD is catalyzed by nicotinamide mononucleotide adenylyl transferases (NMNATs). Other sources, such as nicotinic acid (NA) and nicotinamid riboside (NR), are not shown here as they are not affected by senescence, at least from current research. OIS-specific interactions are highlighted in orange, while MiDAS-specific interactions are highlighted in purple. General interactions for both (or other senescent types) remain a black color.

The OIS pathway, induced by Ras singalling in this case, results in the upregulation of HMGA1, and stimulation of the NAMPT enzyme (Nacarelli et al., 2019). Resulting increased levels of NMN (the direct metabolite of NAMPT) translate to increased NAD levels, and a high NAD-NADH ratio. This leads to decreased ADP-ATP levels, which causes a decreased phosphorylated AMPK expression (Nacarelli et al., 2019). This interaction causes increased p38 and p65 activation, and increased NF-κB activity. The NF-κB signalling pathway has been known to play a key role in the promotion of the proinflammatory SASP (Freund et al., 2011). Furthermore, this is correlated with increased expression of interleukins IL1B, IL6 and IL8, all key factors in the proinflammatory wave of the SASP. In addition, Nacarelli et al. (2019) found that the proinflammatory environment created as a result of the increased NAD-NADH ratio leads to acceleration of cancer progression. NAMPT upregulation through HMGA1 also resulted in the expression of senescence markers SA-ß-gal, p16 and p21. The resulting phenotype from this high NAD-NADH ratio is a high proinflammatory SASP.

Malate is another important metabolite in redox reactions and in many senescence types, including OIS and MiDAS. Of interest to NAD metabolism is the malate-aspartate shuttle, where NADH is transferred from the cytosol to the mitochondrial matrix through malate dehydrogenase 1 (MDH1) (Lee et al., 2012). In senescence, levels of MDH1 decrease. On the other hand, decreased activity of MDH1 can induce a senescence response. This reduction in MDH1 activity results in a decreased cytosolic NAD-NADH. Lastly, this inhibition may result in loss of cell proliferation due to the requirement of aspartate synthesis in response to inhibition of the electron transport chain (Birsoy et al., 2015).

Mitochondrial dysfunction-associated senescence (MiDAS), on the other hand, causes a decrease in the NAD-NADH ratio, which induces three main responses: (1) the inhibition of sirtuins, (2) the activation of AMPK and (3) the inhibition of PARP which blocks the NF-kB pathway. First, low levels of NAD+ decrease sirtuin activity. A decrease in the activity of SIRT3 and SIRT5, located in the mitochondria, is associated with the activation of cell senescence (Wiley et al., 2016)). Second, a decreased NAD+/NADH ratio activates AMPK and p53, which inhibits the RNA binding protein Hu antigen R (HuR) from degrading the mRNAs encoding the cyclin-dependent kinase inhibitors, p21 and p16INK4a. This increases the activity of the pRB tumor suppressor, resulting in cell proliferation and growth arrest ((Wiley et al., 2016)). Additionally, p53 activation leads to the release of SASPs that lack IL-1-dependent factors but include the secretion of anti-inflammatory cytokine IL-10 and high levels of the pro-inflammatory cytokines CCL27 and TNF-α (Wiley et al., 2016). The activation of p53 also reduces glycolysis and promotes mitochondrial respiration, by inhibiting phosphoglycercate mutase (PGM) and inducing the expression of synthesis of cytochrome c oxidase 2 (SCO2). Furthermore, p53 activation inhibits the pentose phosphate pathway (PPP) by binding to glucose-6-phosphate dehydrogenase (G6PDH). Lastly, the low NAD+,NADH ratio inhibits ADP-ribose donor for poly-ADP ribose polymerase (PARP), which consecutively inhibits the NF-kB pathway. A downregulated NF-κB pathway then contributes to the pathogenic processes of various inflammatory diseases as well as the expression of various proinflammatory SASPs (Liu et al., 2017).

As visible in this pathway, when senescence is induced by either OIS or MiDAS distinguishable effects on NAD metabolism are evident. Not only do these stimuli release distinct SASPs, but they exhibit distinct responses on the NAD-NADH ratio and subsequent related pathways. While MiDAS leads to a decrease in the NAD-NADH ratio, OIS causes an increase in this ratio and the NAD+ levels.

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  1. Han X, Tai H, Wang X, Wang Z, Zhou J, Wei X, Ding Y, Gong H, Mo C, Zhang J, Qin J, Ma Y, Huang N, Xiang R, Xiao H; ''''; , PubMed Europe PMC Scholia
  2. Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, Gerencser AA, Verdin E, Campisi J; ''Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.''; Cell Metab, 2016 PubMed Europe PMC Scholia
  3. Lee SM, Dho SH, Ju SK, Maeng JS, Kim JY, Kwon KS; ''Cytosolic malate dehydrogenase regulates senescence in human fibroblasts.''; Biogerontology, 2012 PubMed Europe PMC Scholia
  4. Horenstein AL, Sizzano F, Lusso R, Besso FG, Ferrero E, Deaglio S, Corno F, Malavasi F; ''CD38 and CD157 ectoenzymes mark cell subsets in the human corneal limbus.''; Mol Med, 2009 PubMed Europe PMC Scholia
  5. Takebayashi S, Tanaka H, Hino S, Nakatsu Y, Igata T, Sakamoto A, Narita M, Nakao M; ''Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells.''; Aging Cell, 2015 PubMed Europe PMC Scholia
  6. Surjana D, Halliday GM, Damian DL; ''Role of nicotinamide in DNA damage, mutagenesis, and DNA repair.''; J Nucleic Acids, 2010 PubMed Europe PMC Scholia
  7. Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, Aird KM, Iwasaki O, Kossenkov AV, Schultz D, Noma KI, Baur JA, Schug Z, Tang HY, Speicher DW, David G, Zhang R; ''NAD+metabolism governs the proinflammatory senescence-associated secretome.''; Nat Cell Biol, 2019 PubMed Europe PMC Scholia
  8. Wiley CD, Campisi J; ''From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence.''; Cell Metab, 2016 PubMed Europe PMC Scholia
  9. Ohanna M, Giuliano S, Bonet C, Imbert V, Hofman V, Zangari J, Bille K, Robert C, Bressac-de Paillerets B, Hofman P, Rocchi S, Peyron JF, Lacour JP, Ballotti R, Bertolotto C; ''Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS).''; Genes Dev, 2011 PubMed Europe PMC Scholia


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118987view06:52, 7 June 2021Fehrhartconnected unconnected connections and gave pathway nodes shapes
117800view14:12, 22 May 2021EweitzModified title
117799view14:11, 22 May 2021EweitzModified title
115410view11:46, 18 February 2021EgonwMade six more pathways clickable
115381view00:20, 17 February 2021KhanspersOntology Term : 'nicotinamide adenine dinucleotide metabolic pathway' added !
115380view00:18, 17 February 2021KhanspersOntology Term : 'cellular senescence pathway' added !
115379view00:17, 17 February 2021Khanspersfixed unconnected
115122view09:54, 26 January 2021MkutmonModified description
115121view09:53, 26 January 2021MkutmonModified description
115120view09:50, 26 January 2021MkutmonModified description
115119view09:46, 26 January 2021MkutmonModified description
115118view09:44, 26 January 2021MkutmonUpdate description
115117view09:27, 26 January 2021MkutmonModified description
115114view09:05, 26 January 2021PaulaP04Modified description
115110view07:37, 26 January 2021EgonwModified title
115109view07:36, 26 January 2021EgonwNormalized two Ensembl data sources
115031view16:57, 25 January 2021PaulaP04New pathway

External references


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NameTypeDatabase referenceComment
AMPKa1ProteinENSG00000132356 (Ensembl)
AspartateMetabolite35391 (ChEBI)
CCL27GeneProductENSG00000213927 (Ensembl)
Canonical NF-KB PathwayPathwayWP4562 (WikiPathways)
Fatty Acid Beta OxidationPathwayWP143 (WikiPathways)
G6PDHProteinENSG00000160211 (Ensembl)
GLUT1ProteinENSG00000117394 (Ensembl)
GLUT4ProteinENSG00000181856 (Ensembl)
GOT1GeneProductENSG00000120053 (Ensembl)
GOT2GeneProductENSG00000125166 (Ensembl)
GlycolysisPathwaymap00010 (KEGG Pathway)
HMGA1GeneProductENSG00000137309 (Ensembl)
HuRProteinENSG00000066044 (Ensembl)
IL-10ProteinENSGALG00000000892 (Ensembl)
IL1BGeneProductENSG00000125538 (Ensembl)
IL6GeneProductENSG00000136244 (Ensembl)
IL8MetaboliteCHEBI:138181 (ChEBI)
MDH1GeneProductENSG00000014641 (Ensembl)
MDH2GeneProductENSG00000146701 (Ensembl)
MalateMetaboliteCHEBI:30797 (ChEBI)
Mitochondrial Oxidative PhosphorylationPathwayWP623 (WikiPathways)
NADHMetaboliteHMDB01487 (HMDB)
NADMetaboliteHMDB00902 (HMDB)
NAMPTGeneProductENSG00000105835 (Ensembl)
NMNAT2GeneProductENSG00000157064 (Ensembl)
NMNMetaboliteCHEBI:16171 (ChEBI)
OAAMetaboliteCHEBI:132560 (ChEBI)
Oncogene Induced SenescencePathwayWP3308 (WikiPathways)
Oncogene Induced SenescencePathwayWP3308 (WikiPathways)
PARP1GeneProductENSG00000143799 (Ensembl)
PGMMetaboliteCHEBI:33365 (ChEBI)
PRPPMetaboliteCHEBI:17111 (ChEBI)
SCO2GeneProductENSG00000130489 (Ensembl)
SIRT1GeneProductENSG00000096717 (Ensembl)
SIRT2GeneProductENSG00000068903 (Ensembl)
SIRT3GeneProductENSG00000142082 (Ensembl)
SIRT5GeneProductENSG00000124523 (Ensembl)
TCA CyclePathwayWP78 (WikiPathways)
TNF-aProteinENSG000002328 (Ensembl)
TP53GeneProductENSG00000141510 (Ensembl)
Transcription factor p65ProteinQ04206 (Uniprot-TrEMBL)
lactateMetaboliteCHEBI:24996 (ChEBI)
nicotinamideMetaboliteCHEBI:17154 (ChEBI)
p38 MAPKGeneProductQ3C2E3 (Uniprot-TrEMBL)
pRBRnaENSG00000139687 (Ensembl)
pyruvateMetaboliteCHEBI:15361 (ChEBI)

Annotated Interactions

No annotated interactions

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