What is cellular respiration?

Cellular respiration is a fundamental biological process in which cells convert nutrient molecules — primarily glucose — into adenosine triphosphate (ATP), the universal energy currency of the cell. The process occurs in the mitochondria of eukaryotic cells and in the cytoplasm of prokaryotic cells.

The energy released drives essential cellular activities: muscle contraction, active transport, macromolecule synthesis, and the maintenance of ion gradients. Roughly 90% of the ATP a typical human cell uses every day is produced by cellular respiration in the mitochondria.

The cellular respiration equation

The overall balanced equation for aerobic cellular respiration is:

One molecule of glucose plus six molecules of oxygen is converted into six molecules of carbon dioxide, six molecules of water, and energy in the form of ATP. The actual ATP yield depends on the shuttle system used to move cytoplasmic NADH into the mitochondria and on the precise P/O ratio of the electron transport chain.

Aerobic vs anaerobic respiration

Cellular respiration takes two forms depending on whether oxygen is present. The two pathways share glycolysis but diverge afterwards:

The four stages of aerobic cellular respiration

Aerobic cellular respiration is split into four sequential stages. Each stage has its own location, substrate, products, and contribution to overall ATP yield:

Textbook note: Older textbooks cite 36–38 ATP per glucose. Updated P/O ratios — 2.5 ATP per NADH, 1.5 ATP per FADH2 — give the more realistic 30–32 ATP figure used here.

Stage 1: Glycolysis

Glycolysis is the cytoplasmic breakdown of one molecule of glucose (6 carbons) into two molecules of pyruvate (3 carbons each). It is the oldest and most universal energy-yielding pathway in biology and occurs whether oxygen is present or not.

Investment phase (steps 1–5)

The cell spends 2 ATP to prime the glucose molecule for breakdown. Hexokinase phosphorylates glucose to glucose-6-phosphate, which is isomerised to fructose-6-phosphate by phosphoglucose isomerase, and then phosphorylated again by phosphofructokinase-1 (PFK-1) — the rate-limiting and most regulated enzyme of glycolysis. The resulting fructose-1,6-bisphosphate is cleaved by aldolase into two triose phosphates, which are interconverted by triose phosphate isomerase.

Payoff phase (steps 6–10)

Each triose phosphate is oxidised by GAPDH with reduction of NAD+ to NADH, then dephosphorylated through reactions catalysed by phosphoglycerate kinase, phosphoglycerate mutase, enolase, and finally pyruvate kinase to yield pyruvate. Substrate-level phosphorylation produces 4 ATP across both triose molecules — a net gain of 2 ATP after the initial investment.

Net per glucose: 2 pyruvate, 2 NADH, 2 ATP.

Deep dive: For a full enzyme-by-enzyme walkthrough with diagram and regulation, see our companion guide: The 10 Steps of Glycolysis: Enzymes, Diagram & ATP Yield.

Stage 2: Pyruvate oxidation (the link reaction)

Pyruvate must travel from the cytoplasm into the mitochondrial matrix, where it is converted into acetyl-CoA by the pyruvate dehydrogenase complex (PDC) — a three-enzyme assembly comprising pyruvate dehydrogenase (E1), dihydrolipoamide transacetylase (E2), and dihydrolipoamide dehydrogenase (E3). One CO2 is released and one NADH is generated for each pyruvate.

PDC is heavily regulated: it is inhibited by its own products (acetyl-CoA, NADH, ATP) and activated when ADP and pyruvate are high. Defects in PDC cause severe lactic acidosis and neurodegenerative disease, and PDC activity is now studied as a potential metabolic target in cancer.

Net per glucose (both pyruvates): 2 Acetyl-CoA, 2 NADH, 2 CO2.

Stage 3: The citric acid cycle (Krebs cycle / TCA cycle)

Acetyl-CoA enters the citric acid cycle by combining with oxaloacetate to form citrate. Each turn of the cycle releases two molecules of CO2 and harvests high-energy electrons as NADH and FADH2. Because each glucose molecule yields two acetyl-CoA, the cycle turns twice per glucose.

Acetyl-CoA combines with oxaloacetate to form citrate via citrate synthase; aconitase rearranges citrate to isocitrate; isocitrate dehydrogenase and the α-ketoglutarate dehydrogenase complex each generate NADH and release CO2; succinate dehydrogenase generates FADH2; fumarase hydrates fumarate to malate; and malate dehydrogenase regenerates oxaloacetate to start the next turn.

Per cycle turn (per acetyl-CoA)

• 3 NADH (from isocitrate, α-ketoglutarate and malate)
• 1 FADH2 (from succinate)
• 1 GTP/ATP (substrate-level phosphorylation at succinyl-CoA)
• 2 CO2 released

Net per glucose (both turns): 6 NADH, 2 FADH2, 2 ATP, 4 CO2.

Stage 4: Oxidative phosphorylation

Oxidative phosphorylation captures the energy stored in NADH and FADH2 as ATP. It has two coupled parts:

The electron transport chain (ETC)

Four protein complexes embedded in the inner mitochondrial membrane (Complexes I–IV) pass electrons from NADH and FADH2 down a chain of redox carriers to oxygen, the final electron acceptor. As the electrons descend, Complexes I, III and IV pump protons (H+) from the matrix into the intermembrane space, creating an electrochemical gradient — the proton-motive force.

Chemiosmosis & ATP synthase

Protons flow back into the matrix down their gradient through ATP synthase, a rotary motor enzyme that uses the energy of proton flux to phosphorylate ADP into ATP. At the end of the chain, four electrons combine with one O2 and four H+ to form two H2O.

Net per glucose: ~26–28 ATP (using P/O ratios of 2.5 for NADH and 1.5 for FADH2).

Net ATP calculation per glucose

Anaerobic respiration & fermentation

When oxygen is unavailable, the electron transport chain stalls, NADH cannot be reoxidised, and the citric acid cycle grinds to a halt. Cells then rely on glycolysis alone, regenerating NAD+ by fermenting pyruvate.

Lactate fermentation

In skeletal muscle during intense exercise and in many bacteria, lactate dehydrogenase reduces pyruvate to lactate, regenerating NAD+ so glycolysis can continue. Lactate is later cleared by the liver via the Cori cycle.

Ethanol fermentation

Yeast and some bacteria decarboxylate pyruvate to acetaldehyde, which is then reduced to ethanol, regenerating NAD+. This pathway powers the brewing and bread-making industries.

Alternative electron acceptors in bacteria

Some prokaryotes use nitrate (NO3-), sulfate (SO42-), or sulfur as final electron acceptors instead of oxygen, producing nitrogen gas or hydrogen sulfide as byproducts. These pathways underpin biogeochemical cycling in soils and sediments.

Regulation of cellular respiration

Respiration is tuned at multiple checkpoints to match ATP supply with cellular demand:

• PFK-1 in glycolysis is inhibited by high ATP and citrate, activated by AMP and fructose-2,6-bisphosphate.
• Pyruvate dehydrogenase is inhibited by its products (acetyl-CoA, NADH, ATP) and by phosphorylation.
• The citric acid cycle is throttled by NADH/NAD+ ratio and by ATP levels.
• Oxidative phosphorylation is limited by ADP availability and oxygen tension.
• Hormonal control via insulin and glucagon regulates substrate supply, while transcription factors like HIF-1α and PGC-1α reshape metabolic capacity over hours to days.

The Warburg effect & mitochondrial dysfunction

Otto Warburg observed in the 1920s that tumour cells preferentially perform glycolysis followed by lactate fermentation — even when oxygen is plentiful. This shift, the Warburg effect, is now considered a metabolic hallmark of cancer and underpins clinical FDG-PET imaging.

Mitochondrial dysfunction is also implicated in inherited mitochondrial disorders (MELAS, MERRF, Leigh syndrome, Kearns–Sayre), neurodegenerative disease (Alzheimer's, Parkinson's), insulin resistance, and ageing. These conditions are now active drug targets — many of which require precise quantification of metabolic flux to study.

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