Tricarboxylic acid cycle and lactate dehydrogenase-associated metabolic pathways (TCA/LDH pathways)

The tricarboxylic acid (TCA) cycle and lactate dehydrogenase (LDH)-associated pathways represent the central hub of cellular energy metabolism and biosynthetic flux. In healthy cells, the TCA cycle facilitates oxidative phosphorylation in the mitochondria to maximize ATP production from glucose-derived pyruvate (NCBI, StatPearls). However, in many disease states, particularly cancer, cells undergo metabolic reprogramming known as the Warburg effect, where they prioritize glycolysis and the conversion of pyruvate to lactate via LDH even in the presence of oxygen (Vander Heiden et al., Science, 2009). This shift provides the necessary carbon skeletons for rapid biomass accumulation and alters the cellular redox state to support proliferation. Therapeutic strategies targeting these pathways do not target the 'pathway' as a single entity but rather focus on specific rate-limiting enzymes such as LDH, isocitrate dehydrogenase (IDH), or glutaminase to starve diseased cells of energy and building blocks (Valvona et al., 2016). While promising in oncology, targeting these fundamental metabolic routes carries risks of systemic toxicity due to the reliance of healthy tissues, such as the brain and heart, on efficient mitochondrial metabolism.

Other names

Krebs cycleCitric acid cycleWarburg effect pathwaysGlycolytic-TCA fluxPyruvate-lactate metabolism

Inhibition of specific rate-limiting enzymes within the TCA cycle or the conversion of pyruvate to lactate to disrupt cellular energy metabolism, biosynthetic precursors, and redox homeostasis.