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

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3, 77755575521, 5585857788655785554, 98567Cell SenescencePromotion ofCancer ProgressionCommon forboth pathwaysPentose PhospatePathwayMitochondrial Dysfunction-Associated SenescenceMITOCHONDRIAGrowth ArrestCYTOPLASMSIRT1TNF-aCCL27PARP1pyruvatePRPPNADGLUT1Oncogene Induced SenescenceAMPKa1SA-B-GalpRBPGMp38 MAPKIL6TP53NMNAT2ADP/ATPCanonical NF-KB PathwaylactateNAMPTOAAGOT1SIRT2AspartateGlycolysisMDH1p16GOT2p21MDH2SIRT5MalateNADHFatty AcidBeta OxidationG6PDHSIRT3nicotinamideHuRHMGA1SCO2IL1BNMNTranscription factor p65IL-10IL8GLUT4High proinflammatory SASP5MalateOAAAspartateMitochondrial Oxidative PhosphorylationTCA Cycle5NAD/NADHOncogene Induced SenescenceMitochondrial Dysfunction-Associated Senescence


Description

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).

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Bibliography

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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

History

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CompareRevisionActionTimeUserComment
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

DataNodes

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NameTypeDatabase referenceComment
ADP/ATP
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)
NAD/NADH
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)
SA-B-Gal
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)
p16
p21
p38 MAPKGeneProductQ3C2E3 (Uniprot-TrEMBL)
pRBRnaENSG00000139687 (Ensembl)
pyruvateMetaboliteCHEBI:15361 (ChEBI)

Annotated Interactions

No annotated interactions

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