This paper is a narrative review of the mammalian tricarboxylic acid (TCA) cycle—also known as the Krebs cycle or citric acid cycle—integrating classical biochemistry with modern insights from cell biology, immunology, and cancer research. Rather than portraying the TCA cycle as a simple, linear pathway for ATP production, the authors show it functions as a highly regulated and adaptable metabolic network. TCA intermediates such as citrate, α-ketoglutarate, succinate, fumarate, and acetyl-CoA act as signaling molecules that directly influence gene expression, epigenetic regulation, immune responses, stem cell differentiation, and tumor behavior. The review highlights how changes in substrate availability, redox state, and mitochondrial flux can reprogram cellular function well before overt disease appears. Overall, the paper reframes the TCA cycle as a central control system linking nutrient status to cell fate, positioning mitochondrial metabolism as a causal driver of physiology and pathology—not merely a downstream reflection of it.

https://www.sciencedirect.com/science/article/pii/S0021925822012819