Bioscience Evidence 2024, Vol.14, No.3, 110-121 http://bioscipublisher.com/index.php/be 110 Research Report Open Access The Central Role of the Citric Acid Cycle in Energy Metabolism: From Metabolic Intermediates to Regulatory Mechanisms Rui Wang, Linn Lou Biotechnology Research Center, Cuixi Academy of Biotechnology, Zhuji, 311800, China Corresponding author email: linn.lou@jicat.org Bioscience Evidence, 2024, Vol.14, No.3 doi: 10.5376/be.2024.14.0013 Received: 09 Apr., 2024 Accepted: 13 May, 2024 Published: 28 May, 2024 Copyright © 2024 Wang and Lou, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Wang R., and Lou L., 2024, The central role of the citric acid cycle in energy metabolism: from metabolic intermediates to regulatory mechanisms, Bioscience Evidence, 14(3): 110-121 (doi: 10.5376/be.2024.14.0013) Abstract The citric acid cycle (TCA) plays a crucial central role in cellular energy metabolism by linking the breakdown of carbohydrates, fats, and proteins, thereby promoting the generation of ATP and maintaining cellular energy homeostasis. This study systematically explores the metabolic intermediates of the citric acid cycle and its complex regulatory mechanisms, revealing its multifaceted functions in energy metabolism, cellular signaling, and biosynthesis. The results indicate that the citric acid cycle is not only vital for energy production but also directly participates in various biosynthetic pathways within the cell by providing precursors for amino acids, fatty acids, and other essential biomolecules. Additionally, the intermediates of the citric acid cycle play important roles in regulating immune responses, mitophagy, cellular stress responses, and metabolic reprogramming, contributing to cellular stability in response to environmental changes. This study provides new insights into the mechanisms of metabolic disorders and disease development, offering a theoretical basis for the development of novel therapeutic strategies. By gaining an in-depth understanding of the multi-layered regulatory mechanisms of the citric acid cycle, this study will advance scientific studies and practical applications in related fields. Keywords Citric acid cycle; Energy metabolism; Metabolic intermediates; Regulatory mechanisms; Cellular homeostasis; Metabolic engineering 1 Introduction The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle, is a fundamental metabolic pathway that plays a crucial role in cellular respiration (Guo et al., 2022). Discovered by Hans Krebs in 1937, this cycle involves a series of enzyme-catalyzed chemical reactions that are pivotal for the aerobic oxidation of fuel molecules. Krebs identified that citrate is formed from oxaloacetate and acetyl-CoA, leading to the realization that this pathway is a cyclic sequence of reactions essential for energy production in aerobic organisms (Bodner, 1986; Choi et al., 2020). The TCA cycle is distinct from glycolysis in that it is a cyclic rather than a linear pathway, and it occurs within the mitochondria, tightly coupled with the electron transport chain and oxidative phosphorylation. The citric acid cycle is central to energy metabolism, facilitating the controlled combustion of carbohydrates, fats, and proteins into carbon dioxide and water, while generating high-energy electron carriers NADH and FADH2. These carriers subsequently donate electrons to the electron transport chain, driving the production of ATP, the primary energy currency of the cell (Fernie et al., 2004; MacLean et al., 2023). Beyond its role in energy production, the TCA cycle is involved in various biosynthetic processes, providing precursors for amino acids, nucleotide bases, and other essential biomolecules (Iñigo et al., 2021). The cycle's intermediates also play significant roles in cellular signaling and regulation, influencing processes such as mitophagy, cellular stress responses, and metabolic reprogramming in response to environmental changes (Mccammon et al., 2003; Franco and Serrano-Marín, 2022; MacLean et al., 2023). This study elucidates the central role of the citric acid cycle in energy metabolism, with a focus on its metabolic intermediates and regulatory mechanisms. By exploring the complex network of reactions and their regulation, the study aims to provide a comprehensive understanding of how the TCA cycle integrates with other metabolic pathways to maintain cellular homeostasis and respond to physiological demands. The study seeks to uncover new
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