WP5050 - TCA cycle in senescence - 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