TCA cycle in senescence

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

丙酮酸脱氢酶（PDH）是三羧酸循环（TCA循环）中的核心酶之一，因其将丙酮酸转化为乙酰辅酶A而备受瞩目。该酶的活性有利于TCA循环的进行。PDH受PDH激酶（PDK）的负调控和PDH磷酸酶（PDP）的正调控。在氧化应激诱导的衰老（OIS）中，PDK与PDP的表达分别受到抑制和激活，尤其是在癌基因BRAFV600E的作用下（James等，2015；Wiley & Campisi，2016）。由于这些调控机制，PDH成为TCA循环在OIS中的关键介质。苹果酸酶（ME）是TCA循环中的另一关键酶。p53与ME之间存在相互调控关系，这种调控通过AMPK的激活实现。ME的下调导致p53介导的衰老诱导，而上调则可以抑制这一过程（Jiang等，2013；Wiley & Campisi，2016）。由于ME利用NAD+/NADP+并产生NADH/NADPH，酶的下调同样会影响NADPH依赖的机制，包括抗氧化防御系统。这一过程进而可能引起活性氧（ROS）的积累，通过AMPK激活p53，导致衰老（Wiley & Campisi，2016）。在OIS中，观察到TCA中间产物的积累，包括α-酮戊二酸、柠檬酸和苹果酸（Kaplon等，2013）。进一步的研究表明，α-酮戊二酸的升高对转录调控具有影响（Salama等，2014）。脂质也是TCA循环的输入之一，在OIS中观察到脂肪酸氧化增加（Sabbatinelli等，2019）。苹果酸脱氢酶（MDH1）在TCA循环中也发挥着重要作用，并参与苹果酸-天冬氨酸穿梭系统。在DNA损伤诱导的和增殖耗竭诱导的衰老细胞中观察到该酶水平降低。MDH1的下调也影响NAD+/NADH比例，这一比例与衰老相关。苹果酸-天冬氨酸穿梭系统中的其他酶，如天冬氨酸转氨酶（GOT1），也影响这一比例。关于影响衰老中NAD代谢的因素，可在https://www.wikipathways.org/index.php/Pathway:WP5046中找到更详细的讨论。