TCA cycle in senescence (WP5050)

Homo sapiens

Pyruvate dehydrogenase (PDH) is a central enzyme in relation to the TCA cycle, as it converts pyruvate into acetyl-CoA. Its activity favours TCA cycle activity. PDH is downregulated by PDH kinase (PDK) and upregulated by PDH phosphatase (PDP). PDK and PDP are respectively down and upregulated in OIS, in particular in the case of the oncogene BRAFV600E (James et al., 2015; Wiley & Campisi, 2016). Due to these regulatory mechanisms, PDH is a crucial mediator of OIS for TCA activity. Malic enzyme (ME) is another crucial enzyme in the TCA cycle. There appears to be a reciprocal regulation between p53 and ME, mediated through AMPK activation. Downregulation of ME leads to p53-mediated induction of senescence, while upregulation can suppress it (Jiang et al., 2013; Wiley & Campisi, 2016). Because ME uses NAD+/NADP+ and produces NADH/NADPH, downregulation of the enzyme also affects NADPH-dependent mechanisms, including antioxidant defenses. This in turn can cause accumulation of reactive oxygen species (ROS), which activate p53 through AMPK and cause senescence (Wiley & Campisi, 2016). In OIS, accumulation of TCA intermediates has been observed, including alpha-ketoglutarate, citrate and malate (Kaplon et al., 2013). Further research showed that increased alpha-ketoglutarate has an effect on transcriptional regulation (Salama et al., 2014). Lipids are also part of the input of the TCA cycle, and fatty acid oxidation has been observed to increase in OIS (Sabbatinelli et al., 2019). Malate dehydrogenase (MDH1) also plays an important role in the TCA cycle and is part of the malate-aspartate shuttle. Lower levels of the enzyme were observed in DNA-damage induced and proliferative exhaustion-induced senescent cells. Downregulation of MDH1 also affects the NAD+/NADH ratio, known to be related to senescence. Other enzymes of the malate-aspartate shuttle also affect this ratio, such as the aspartate aminotransferase (GOT1). Factors influencing NAD metabolism in senescence have been addressed in more details in https://www.wikipathways.org/index.php/Pathway:WP5046

Authors

Wayan Monet , Alex Pico , Egon Willighagen , Friederike Ehrhart , Eric Weitz , and Martina Summer-Kutmon

Activity

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Organisms

Homo sapiens

Communities

Annotations

Pathway Ontology

cellular senescence pathway citric acid cycle pathway classic metabolic pathway

Participants

Label Type Compact URI Comment
ROS Metabolite chebi:26523
AOA Metabolite chebi:40823
NADH Metabolite chebi:16908
alpha-ketoglutarate Metabolite chebi:16810
Acetyl-CoA Metabolite hmdb:HMDB01206
Oxaloacetate Metabolite chebi:30744
NADP+ Metabolite chebi:18009
Glucose Metabolite chebi:17234
Pyruvate Metabolite chebi:15361
Lipids Metabolite chebi:18059
Fumarate Metabolite chebi:29806
Malate Metabolite chebi:30797
NAD+ Metabolite chebi:15846
NADPH Metabolite hmdb:HMDB00221 Mitochondrial NADPH
FH GeneProduct ensembl:ENSG00000091483
BRAF GeneProduct ensembl:ENSG00000157764
TP53 GeneProduct ensembl:ENSG00000141510
MDH1 GeneProduct ensembl:ENSG00000014641
PDH GeneProduct ensembl:ENSG00000131828
ME2 GeneProduct ensembl:ENSG00000082212
GOT1 GeneProduct ensembl:ENSG00000120053
PDP2 GeneProduct ensembl:ENSG00000172840
PDK1 GeneProduct ensembl:ENSG00000152256
ME1 GeneProduct ensembl:ENSG00000065833

References

  1. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Jiang P, Du W, Mancuso A, Wellen KE, Yang X. Nature. 2013 Jan 31;493(7434):689–93. PubMed Europe PMC Scholia
  2. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G, et al. Nature. 2013 Jun 6;498(7452):109–12. PubMed Europe PMC Scholia
  3. Pyruvate as a pivot point for oncogene-induced senescence. Olenchock BA, Vander Heiden MG. Cell. 2013 Jun 20;153(7):1429–30. PubMed Europe PMC Scholia
  4. Cellular senescence and its effector programs. Salama R, Sadaie M, Hoare M, Narita M. Genes Dev. 2014 Jan 15;28(2):99–114. PubMed Europe PMC Scholia
  5. From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence. Wiley CD, Campisi J. Cell Metab. 2016 Jun 14;23(6):1013–21. PubMed Europe PMC Scholia
  6. Mechanisms and functions of cellular senescence. Herranz N, Gil J. J Clin Invest. 2018 Apr 2;128(4):1238–46. PubMed Europe PMC Scholia