Mitochondria, as signaling organelles, play a crucial role in regulating cellular functions and cell fate. Recent studies have highlighted the importance of TCA cycle intermediates, traditionally thought to be involved in biosynthesis, as signaling molecules that control chromatin modifications, DNA methylation, the hypoxic response, and immunity. This review discusses how different TCA cycle metabolites, such as acetyl-CoA, α-ketoglutarate (α-KG), succinate, fumarate, and itaconate, control cellular function and fate through various mechanisms. These metabolites can influence gene expression, chromatin dynamics, and immune responses, thereby affecting physiology and disease. For example, acetyl-CoA regulates histone acetylation, which impacts gene expression and cell proliferation. α-KG is essential for hydroxylation reactions and epigenetic modifications, while succinate and fumarate can inhibit prolyl-hydroxylases, leading to HIF-1α stabilization and pseudohypoxia. Itaconate, an immunomodulator, can induce electrophilic stress and dampen inflammation. The review also explores the bidirectional regulation between mitochondria and the nucleus, emphasizing the importance of TCA cycle metabolites in maintaining cellular homeostasis and responding to environmental cues. Overall, the TCA cycle metabolites serve as key signaling molecules that integrate metabolic and signaling pathways to control cellular functions and diseases.Mitochondria, as signaling organelles, play a crucial role in regulating cellular functions and cell fate. Recent studies have highlighted the importance of TCA cycle intermediates, traditionally thought to be involved in biosynthesis, as signaling molecules that control chromatin modifications, DNA methylation, the hypoxic response, and immunity. This review discusses how different TCA cycle metabolites, such as acetyl-CoA, α-ketoglutarate (α-KG), succinate, fumarate, and itaconate, control cellular function and fate through various mechanisms. These metabolites can influence gene expression, chromatin dynamics, and immune responses, thereby affecting physiology and disease. For example, acetyl-CoA regulates histone acetylation, which impacts gene expression and cell proliferation. α-KG is essential for hydroxylation reactions and epigenetic modifications, while succinate and fumarate can inhibit prolyl-hydroxylases, leading to HIF-1α stabilization and pseudohypoxia. Itaconate, an immunomodulator, can induce electrophilic stress and dampen inflammation. The review also explores the bidirectional regulation between mitochondria and the nucleus, emphasizing the importance of TCA cycle metabolites in maintaining cellular homeostasis and responding to environmental cues. Overall, the TCA cycle metabolites serve as key signaling molecules that integrate metabolic and signaling pathways to control cellular functions and diseases.