Bioscience Evidence 2024, Vol.14, No.3, 110-121 http://bioscipublisher.com/index.php/be 114 4.3 Link with fatty acid oxidation Fatty acid oxidation, or beta-oxidation, generates acetyl-CoA, which is a critical substrate for the citric acid cycle. This process occurs in the mitochondria, where fatty acids are broken down into acetyl-CoA units that enter the citric acid cycle, contributing to ATP production through oxidative phosphorylation. The integration of fatty acid oxidation with the citric acid cycle is essential for maintaining energy balance, especially during periods of low carbohydrate availability (Khan et al., 2022). Citrate plays a dual role in metabolism by not only participating in the citric acid cycle but also serving as a shuttle for fatty acid synthesis. When energy levels are high, citrate is exported from the mitochondria to the cytosol, where it is cleaved by ATP-citrate lyase to generate acetyl-CoA and oxaloacetate. The acetyl-CoA produced in this manner is a precursor for fatty acid synthesis, linking the citric acid cycle to lipid biosynthesis and storage (Roosterman and Cottrell, 2021; Khan et al., 2022). By integrating with glycolysis, amino acid metabolism, and fatty acid oxidation, the citric acid cycle serves as a central hub in cellular energy metabolism, ensuring a coordinated and efficient flow of metabolic intermediates and energy production. 5 Citric Acid Cycle and Cellular Energy Homeostasis 5.1 Role in ATP production The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle, is a central metabolic pathway that plays a crucial role in cellular energy production. It is responsible for the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins into carbon dioxide and water, while generating high-energy electron carriers NADH and FADH2 (Figure 2). These carriers subsequently donate electrons to the oxidative phosphorylation pathway, leading to the production of ATP, the primary energy currency of the cell (Guo et al., 2022). The efficient conversion of metabolic intermediates into ATP through the TCA is essential for maintaining cellular energy homeostasis and supporting various cellular functions (Matschinsky and Wilson, 2019). Figure 2 A schematic depicting the TCA cycle and anaplerotic pathways (Adopted from Guo et al., 2022) Image caption: The figure details how pyruvate, derived from glycolysis, is converted into acetyl-CoA by the pyruvate dehydrogenase complex (PDHC), which then enters the TCA cycle. Additionally, the figure illustrates how the citrate-malate shuttle regenerates cytosolic NAD+, supporting lipid biosynthesis and protein acetylation. The image reveals the crucial role of the citrate-malate shuttle in cellular metabolic reprogramming, providing essential visual support for understanding the mechanisms that determine cell fate (Adapted from Guo et al., 2022)
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