Bioscience Evidence 2024, Vol.14, No.3, 110-121 http://bioscipublisher.com/index.php/be 115 5.2 Contribution to redox balance The TCA is integral to maintaining cellular redox balance by regulating the levels of NADH and NADPH, which are crucial for various anabolic and catabolic processes. NADH, produced during the TCA, is a key electron donor in the mitochondrial electron transport chain, facilitating ATP production while also generating reactive oxygen species (ROS) as by-products. To mitigate the potential damage caused by ROS, cells employ antioxidant systems that rely on NADPH, another critical cofactor produced through metabolic pathways interconnected with the TCA (Shimizu and Matsuoka, 2019). The balance between NADH and NADPH is vital for cellular redox homeostasis, enabling cells to adapt to oxidative stress and maintain metabolic flexibility (Cho et al., 2020; Selinski and Scheibe, 2020). 5.3 Impact on cellular response to energy stress The TCA also plays a pivotal role in the cellular response to energy stress. Under conditions of energy deficiency, such as during intense physical activity or caloric restriction, the TCA can adjust its activity to optimize energy production and support cellular survival. For instance, the transcriptional coactivator PGC-1α is activated in response to energy stress and enhances the expression of genes involved in mitochondrial biogenesis and oxidative metabolism, thereby boosting the capacity for ATP production and ROS detoxification (Shelbayeh et al., 2023). Additionally, metabolic intermediates of the TCA, such as succinate and fumarate, can act as signaling molecules that modulate cellular responses to stress, including inflammation and immune function (Patil et al., 2019). These adaptive mechanisms underscore the central role of the TCA in maintaining cellular energy homeostasis and resilience under varying metabolic conditions (Cani et al., 2019; Ghosh-Choudhary et al., 2020). 6 Citric Acid Cycle in Different Physiological and Pathological Conditions 6.1 Adaptation of the citric acid cycle during exercise During exercise, the citric acid cycle (TCA) adapts to meet the increased energy demands of the body. A study on hepatic metabolism during exercise revealed that there is a pronounced hepatic uptake of lactate, pyruvate, various amino acids, and dicarboxylic acids, indicating a high demand for gluconeogenic substrates and an increase in anaplerotic reactions of the TCA. This adaptation ensures a continuous supply of energy substrates to support prolonged physical activity (Plomgaard et al., 2018). Additionally, medium-chain fatty acids such as caproic acid are taken up by the liver, highlighting their role in regulating gluconeogenesis and mitochondrial substrate oxidation during exercise. 6.2 Changes in the citric acid cycle in metabolic disorders Metabolic disorders can significantly alter the function and regulation of the TCA. For instance, genetic variants in the TCA have been linked to colorectal cancer susceptibility. A study identified significant interactions between single nucleotide polymorphisms (SNPs) in the TCA and factors such as obesity, energy intake, and physical activity, which influence the risk of colorectal cancer. These findings suggest that individual differences in energy metabolism, influenced by genetic variations in the TCA, can contribute to the development of metabolic disorders and associated diseases (Cho et al., 2020). Furthermore, in veterans with Gulf War illness, relationships among TCA markers were found to shift, indicating possible alterations in bioenergetic pathways in this condition (Golomb et al., 2021). 6.3 Role in aging and neurodegenerative diseases The TCA also plays a crucial role in aging and neurodegenerative diseases. As organisms age, the efficiency of the TCA can decline, leading to reduced energy production and increased oxidative stress. This decline is associated with various age-related diseases, including neurodegenerative disorders. The regulation of leukocyte function by TCA intermediates such as succinate, itaconate, citrate, and fumarate has been shown to mediate important cellular functions during infection and inflammation, which are processes often dysregulated in aging and neurodegenerative diseases (Patil et al., 2019). Additionally, the gut microbiome, which influences host metabolism through the production of metabolites that interact with the TCA, has been implicated in the regulation of systemic energy expenditure and may play a role in the aging process and the development of neurodegenerative diseases (Cani et al., 2019).
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