Cellular Respiration & the Krebs Cycle: Eight Steps to ATP

A cycle, not a chain — and that's the whole trick

The citric acid cycle — also called the Krebs cycle after Hans Krebs, who worked out its steps in 1937, or the TCA cycle — runs in the mitochondrial matrix and takes in acetyl-CoA, the universal two-carbon fuel fragment produced from breaking down glucose, fatty acids or amino acids. What makes it a cycle rather than a linear pathway is that its very first step combines acetyl-CoA with a four-carbon molecule called oxaloacetate to form six-carbon citrate, and eight steps later the cycle's last reaction regenerates that same oxaloacetate, ready to accept the next acetyl-CoA. The four-carbon carrier is never consumed — it's continuously reused, turn after turn, which is why a fixed, small pool of intermediates can process an essentially unlimited stream of incoming fuel.

Where the carbon goes, and where the energy goes

Across one full turn, the two carbons that entered as acetyl-CoA leave as two molecules of CO2 — released at the isocitrate dehydrogenase and α-ketoglutarate dehydrogenase steps — which is the direct biochemical source of the carbon dioxide a cell (and, in aggregate, an entire organism) exhales. The chemical energy released as those bonds are broken doesn't mostly leave as heat; it's captured by reducing electron-carrier cofactors: three molecules of NAD+ are reduced to NADH, one molecule of FAD is reduced to FADH2, and one substrate-level phosphorylation step directly generates one GTP (or ATP, in some tissues). The cycle's direct ATP-equivalent yield is small — the electron carriers are the real payload.

// one turn of the citric acid cycle, net:
acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2 H2O
  → 2 CO2 + 3 NADH + FADH2 + GTP + CoA + 3 H+

// those NADH / FADH2 feed the electron transport chain (needs O2):
NADH  → ETC → ~2.5 ATP equivalents (via oxidative phosphorylation)
FADH2 → ETC → ~1.5 ATP equivalents
// this downstream step is where the large majority of usable ATP is actually made

Why the cycle can't run without oxygen — even though O2 never appears in it

No step of the citric acid cycle itself consumes oxygen, which surprises many students given how tightly the cycle is associated with aerobic respiration. The dependency is indirect but absolute: three cycle steps require oxidized NAD+ (and one requires FAD) as a reactant, and the only way those cofactors get reoxidized in a cell doing aerobic metabolism is by handing their electrons to the electron transport chain, which ultimately needs O2 as the final electron acceptor at Complex IV. Cut off oxygen and the electron transport chain backs up almost immediately; NADH and FADH2 have nowhere to unload their electrons, so the cell's entire pool of NAD+ and FAD gets trapped in its reduced form, and the Krebs cycle grinds to a halt for lack of an oxidized cofactor to react with — not for lack of fuel, but for lack of somewhere to put the electrons.

A hub, not just a furnace

Beyond energy extraction, the cycle's eight intermediates double as a supply depot for biosynthesis, which is part of why cells keep it running even when energy demand is modest. Citrate can be exported to the cytoplasm as a starting material for fatty acid synthesis; α-ketoglutarate and oxaloacetate are the direct precursors for the amino acids glutamate and aspartate; succinyl-CoA feeds heme synthesis for hemoglobin and cytochromes. Pulling intermediates out for these side reactions — an cataplerotic process — would eventually stall the cycle if the pool weren't topped back up, so cells run compensating anaplerotic reactions (like pyruvate carboxylase converting pyruvate directly to oxaloacetate) to replenish whatever biosynthesis siphons off, keeping the cycle's core pool of intermediates roughly constant even as it also acts as a raw-materials warehouse.

Frequently asked questions

Try it live

Every intermediate above runs live in Cellular Respiration — Krebs Cycle. Cut oxygen supply mid-run and watch NAD+ run out, the cycle stall, and CO2 output flatline.