The oxygen we breathe is ultimately used in mitochondria to “burn” nutrients. The citric acid (TCA) cycle unveiled by Dr. Krebs starts with acetyl-CoA—derived from sugars, fats and proteins—and proceeds through eight chemical steps (citrate → isocitrate, etc.) before regenerating oxaloacetate. Along the way, electron carriers such as NADH and FADH₂ are generated and later drive ATP production. Understanding this cycle is essential for studying metabolic diseases like diabetes or cancer, and it informs drug discovery and nutritional guidance.

The TCA cycle begins with the condensation of acetyl-CoA and oxaloacetate to form citrate, proceeds through two oxidative decarboxylations yielding succinyl-CoA, and eventually regenerates oxaloacetate. Each turn produces 3 NADH, 1 FADH₂, and 1 GTP (ATP equivalent), which feed electrons into oxidative phosphorylation, giving roughly 10 ATP equivalents per cycle. The pathway is amphibolic, supplying carbon skeletons for amino acids, heme and fatty-acid biosynthesis. Regulation involves allosteric control (e.g., by ATP/ADP ratios) and Ca²⁺-dependent dephosphorylation. Krebs’ work established the paradigm of cyclic metabolic pathways and spurred advances in isotope tracers and spectroscopic analysis.

Krebs combined tissue-slice manometry with organic-acid titrations and inferred catalytic oxaloacetate regeneration from O₂ uptake patterns. Kinetic assays on rat-liver mitochondrial extracts allowed him to formulate the cyclic pathway model. Subsequent ¹⁴C-acetate tracer studies showed CO₂ release profiles matching theoretical predictions, validating the TCA-cycle hypothesis. Contemporary work focuses on fluctuating cofactor pools, late-intermediate acetylation, and anaplerotic supply via mito-cytosolic shuttles; the cycle now figures prominently in signalling and epigenetic modification platforms.