Glycolysis in senescence (Homo sapiens)

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4627977831Acidification ofcellular environmentOxygen ConsumptionRateIrradiationWoundhealingReplicativesenescenceTumorigenesisCellenlargementInflammatorysignalling cascadeEvading immuneresponseStressPyruvateLipidsGAPDHSASPPKMSerineAldolaseAMPKPGK1Oncogene inducedsenescenceTP53TCAcycleGlycolysisOxidativestressNF-kBsignallingPyruvate kinaseGlutamineLDHARB1LactateEnolasePGMHexokinaseProteinsG6PDOncogene inducedsenescence5


Glycolysis appears to be upregulated in most senescent phenotypes. This is hypothesized to match with the increased need for proteins and lipids needed for senescence-associated events such as extracellular secretions (SASP) and cell enlargement (Wiley & Campisi, 2016). It is also supposed to cause an increase in NF-κB signalling and cause inflammatory cascades associated with senescence. Glycolysis is also responsible for increased lactate production by producing pyruvate, along with several other mechanisms including upregulated lactate dehydrogenase (LDHA), pyruvate kinase (PKM), serinolysis and glutaminolysis. Pyruvate kinase (PKM) is responsible for the last conversion step of glycolysis, producing pyruvate. The enzyme is upregulated in replicative senescence and leads to increased TCA activity and oxygen consumption rate (Sabbatinelli et al., 2019). Findings were similar in another study on oncogene-induced senescence (OIS) (Dörr et al., 2013). PKM is also thought to increase lactate production indirectly (Zwerschke et al., 2003). In parallel, lactate dehydrogenase (LDHA) is also upregulated, which leads to this increase in lactate levels in senescent cells. Senescence induced by oncogenes also has an impact on serinolysis and glutaminolysis. These are processes in which serine and glutamine are consumed to produce energy. They usually take place in tumour cells as an alternative source of energy, and produce lactate (among others) as a by-product. It has been found that both processes are increased in OIS, and lead to increases in lactate levels (Mazurek et al., 2001). Such increased levels of lactate lead to several events associated with senescence, such as tumorigenesis, wound healing and evasion from immune responses (Nacarelli & Sell, 2017).

The upregulation of several glycolytic enzymes seems to mediate increased glycolysis in various types of induced senescence. Depending on the stimulus, various proteins and genes influence glycolytic rates. For example, in irradiation-induced senescence, this effect seems to be mediated by AMPK activation and NF-kB signalling (Nacarelli & Sell, 2017). Similarly, in OIS, the retinoblastoma protein appears to upregulate glycolytic genes (Nacarelli & Sell, 2017). The very important p53 is known to be a central mediator of senescence, due to its role in cell cycle regulation. It has been found to negatively affect glycolysis (Gu et al., 2018). However it also has an indirect positive effect on it, by activating G6PDH in stressed cells (Jiang et al., 2011). TP53 is therefore thought to have a regulatory role on glycolysis and is interesting in the context of senescence.

While most glycolytic enzymes are upregulated (Zwerschke et al., 2003), GAPDH seems to decrease. This may partially be explained by the sensitivity of the enzyme to oxidative stress.

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  1. Mazurek S, Zwerschke W, Jansen-Dürr P, Eigenbrodt E; ''Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and HPV-16 E7.''; Oncogene, 2001 PubMed Europe PMC Scholia
  2. Gu J, Wang S, Guo H, Tan Y, Liang Y, Feng A, Liu Q, Damodaran C, Zhang Z, Keller BB, Zhang C, Cai L; ''Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis.''; Cell Death Dis, 2018 PubMed Europe PMC Scholia
  3. Sabbatinelli J, Prattichizzo F, Olivieri F, Procopio AD, Rippo MR, Giuliani A; ''Where Metabolism Meets Senescence: Focus on Endothelial Cells.''; Front Physiol, 2019 PubMed Europe PMC Scholia
  4. Birgit Veldman; ''Metabolic hallmarks of cellular senescence: highlighting the role of intracellular pathways in various senescent phenotypes''; , 2020
  5. Zwerschke W, Mazurek S, Stöckl P, Hütter E, Eigenbrodt E, Jansen-Dürr P; ''Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence.''; Biochem J, 2003 PubMed Europe PMC Scholia
  6. Wiley CD, Campisi J; ''From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence.''; Cell Metab, 2016 PubMed Europe PMC Scholia
  7. Nacarelli T, Sell C; ''Targeting metabolism in cellular senescence, a role for intervention '';, 2017
  8. Dörr JR, Yu Y, Milanovic M, Beuster G, Zasada C, Däbritz JH, Lisec J, Lenze D, Gerhardt A, Schleicher K, Kratzat S, Purfürst B, Walenta S, Mueller-Klieser W, Gräler M, Hummel M, Keller U, Buck AK, Dörken B, Willmitzer L, Reimann M, Kempa S, Lee S, Schmitt CA; ''Synthetic lethal metabolic targeting of cellular senescence in cancer therapy.''; Nature, 2013 PubMed Europe PMC Scholia
  9. Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X; ''p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase.''; Nat Cell Biol, 2011 PubMed Europe PMC Scholia


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118985view06:45, 7 June 2021Fehrhartconnected unconnected connection
115339view14:07, 14 February 2021EgonwMade a few more pathway clickable
115220view20:15, 5 February 2021AlexanderPicoOntology Term : 'classic metabolic pathway' added !
115219view20:14, 5 February 2021AlexanderPicoOntology Term : 'cellular senescence pathway' added !
115113view08:58, 26 January 2021WayanM0
115111view08:54, 26 January 2021WayanM0New pathway

External references


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NameTypeDatabase referenceComment
AMPKProteinQ13131 (Uniprot-TrEMBL)
AldolaseProteinA0A024QZ64 (Uniprot-TrEMBL)
EnolaseProteinA0A024R4F1 (Uniprot-TrEMBL)
G6PDGeneProductENSG00000160211 (Ensembl)
GAPDHGeneProductENSG00000111640 (Ensembl)
GlutamineMetaboliteCHEBI:28300 (ChEBI)
GlycolysisPathwayWP534 (WikiPathways)
HexokinaseProteinA0A024QZK7 (Uniprot-TrEMBL)
LDHAGeneProductENSG00000134333 (Ensembl)
LactateMetaboliteCHEBI:24996 (ChEBI)
LipidsMetaboliteCHEBI:18059 (ChEBI)
NF-kB signallingPathwayWP4562 (WikiPathways)
Oncogene induced senescencePathwayWP3308 (WikiPathways)
Oxidative stressPathwayWP3404 (WikiPathways)
PGK1GeneProductENSG00000102144 (Ensembl)
PGMMetaboliteCHEBI:33365 (ChEBI)
PKMGeneProductENSG00000067225 (Ensembl)
ProteinsMetaboliteCHEBI:36080 (ChEBI)
Pyruvate kinaseProteinA0A024R5Z9 (Uniprot-TrEMBL)
PyruvateMetaboliteCHEBI:15361 (ChEBI)
RB1GeneProductENSG00000139687 (Ensembl)
SASPPathwayWP3391 (WikiPathways)
SerineMetaboliteCHEBI:17822 (ChEBI)
TCA cyclePathwayWP78 (WikiPathways)
TP53GeneProductENSG00000141510 (Ensembl)

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