Bioscience Evidence 2024, Vol.14, No.3, 110-121 http://bioscipublisher.com/index.php/be 116 The citric acid cycle is a central metabolic pathway that adapts to various physiological conditions such as exercise, and its dysregulation is implicated in metabolic disorders, aging, and neurodegenerative diseases. Understanding these adaptations and changes can provide insights into the development of targeted therapies for these conditions. 7 Case Studies 7.1 Citric acid cycle dysfunction in mitochondrial diseases Mitochondrial diseases often involve dysfunctions in the citric acid cycle (TCA), which is crucial for cellular energy production. Dysregulation in the TCA can lead to impaired energy metabolism, contributing to the pathophysiology of various mitochondrial disorders. For instance, mutations in genes encoding TCA enzymes can disrupt the cycle, leading to reduced ATP production and increased oxidative stress. This is evident in conditions such as mitochondrial myopathies and neurodegenerative diseases, where energy-demanding tissues like muscles and the brain are predominantly affected (Dai and Jiang, 2019; Luo et al., 2020). The study found that key mitochondrial enzymes and mitochondrial DNA (mtDNA) mutations drive cancer development by disrupting the TCA cycle and oxidative phosphorylation. For example, mutations in the IDH1/2 genes lead to the accumulation of oncogenic metabolites, which interfere with normal cellular metabolism and promote tumor growth in gliomas and leukemia (Figure 3) (Luo et al., 2020). Additionally, mutations in the SDH and FH enzymes cause abnormal accumulation of metabolites, stabilizing HIF1α and creating a pseudo-hypoxic environment conducive to cancer progression. Furthermore, mitochondrial DNA mutations and defects in the electron transport chain exacerbate these dysfunctions, underscoring the central role of the TCA cycle in maintaining cellular energy homeostasis (Dai and Jiang, 2019; Luo et al., 2020). Figure 3 Dysfunctional tricarboxylic acid (TCA) cycle enzymes in cancers (Adopted from Luo et al., 2020) Image caption: The figure illustrates the mechanism of TCA cycle enzyme dysfunction in cancer. It depicts how mutations in IDH2 lead to the accumulation of 2-hydroxyglutarate (2-HG), which causes epigenetic changes and inhibits SDH, resulting in the accumulation of succinyl-CoA and impaired mitochondrial respiration. Additionally, the figure shows how mutations in SDH and FH cause abnormal accumulation of succinate and fumarate, which stabilizes HIF1α, creating a pseudo-hypoxic state that promotes cancer progression. This figure reveals how the dysfunction of key enzymes in the TCA cycle drives tumorigenesis through oxidative stress and metabolic disturbances (Adapted from Luo et al., 2020)
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