Biochemistry
Cellular Respiration
Glycolysis, Krebs cycle, electron transport — how cells turn glucose into ATP
Cellular respiration extracts energy from glucose to make ATP, the universal cellular fuel. Glycolysis (cytosol) splits glucose to two pyruvate, netting 2 ATP and 2 NADH. Pyruvate enters mitochondria and is converted to acetyl-CoA. Krebs cycle yields 6 NADH, 2 FADH2, 2 GTP per glucose. Electron transport chain uses these reducing equivalents to pump protons; ATP synthase makes ~26-28 ATP via chemiosmosis. Total: ~30-32 ATP per glucose. Defects cause mitochondrial diseases; cancer cells favor aerobic glycolysis (Warburg effect).
- Total ATP per glucose~30-32 (aerobic)
- Glycolysis locationCytosol
- Krebs/ETC locationMitochondrial matrix/inner membrane
- O2 consumption~250 mL/min at rest (adult)
- ETC complexesI-IV plus ATP synthase (V)
- Anaerobic yield2 ATP per glucose
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Why cellular respiration matters
- Lactic acidosis. Sepsis, shock, metformin toxicity, ischemia all elevate lactate.
- Cyanide poisoning. Hydroxocobalamin or sodium thiosulfate antidotes.
- Oncology imaging. FDG-PET exploits the Warburg effect to localize tumors.
- Diabetes drugs. Metformin partially inhibits Complex I, lowering hepatic glucose output.
- Exercise physiology. Anaerobic threshold marks the shift to lactate accumulation.
- Mitochondrial disease. Suspect with multi-organ involvement, lactic acidosis, deafness.
- Statins and CoQ10. Statins reduce CoQ10 synthesis; some patients supplement for myopathy.
Common misconceptions
- "36 ATP" is exact. Real yield is ~30-32 due to proton leak and shuttle costs.
- Lactic acid causes muscle soreness. Soreness is microtrauma; lactate clears within an hour.
- Mitochondria only make ATP. They handle apoptosis, calcium buffering, heme synthesis, steroid synthesis.
- O2 is consumed in glycolysis. O2 is only used at Complex IV.
- Warburg cells lack mitochondria. They have functional mitochondria but choose glycolysis.
- Krebs cycle just makes ATP. Its intermediates feed amino acid synthesis, heme, gluconeogenesis.
Frequently asked questions
What is glycolysis?
10-step pathway in cytosol. Glucose (C6) is phosphorylated by hexokinase (uses 1 ATP), isomerized, phosphorylated again (uses 1 ATP), split to two G3P, then through energy-yielding steps producing 4 ATP and 2 NADH. Net: 2 ATP, 2 NADH, 2 pyruvate. Rate-limiting enzyme: phosphofructokinase-1 (allosterically inhibited by ATP, citrate; activated by AMP, F2,6BP).
What does the Krebs cycle do?
Acetyl-CoA (2C) joins oxaloacetate (4C) to form citrate (6C). Through 8 steps, two CO2 are released and the 4C OAA is regenerated. Each cycle yields 3 NADH, 1 FADH2, 1 GTP/ATP. Per glucose (2 acetyl-CoA): 6 NADH, 2 FADH2, 2 GTP. Located in mitochondrial matrix. Hub for amino acid catabolism and gluconeogenesis precursors.
How does the electron transport chain work?
NADH donates electrons at Complex I; FADH2 at Complex II. Electrons flow through coenzyme Q to Complex III, cytochrome c, Complex IV, finally reducing O2 to water. Complexes I, III, IV pump H+ into intermembrane space, creating an electrochemical gradient. ATP synthase (Complex V) lets H+ flow back, rotating to phosphorylate ADP. Yield: ~2.5 ATP per NADH, 1.5 per FADH2.
What happens without oxygen?
ETC stalls; NADH accumulates; Krebs cycle stops. Pyruvate is reduced to lactate by lactate dehydrogenase, regenerating NAD+ to keep glycolysis running. Yield drops to 2 ATP/glucose. Lactate accumulates, dropping pH (lactic acidosis). Brain tolerates ~3 minutes; muscle can sustain anaerobic work briefly during sprints.
What is the Warburg effect?
Cancer cells preferentially use aerobic glycolysis even with abundant O2. Despite being less efficient (2 vs 32 ATP), it provides biosynthetic intermediates and tolerates hypoxic tumor cores. PET scans use 18F-FDG (a glucose analog) to image high-glycolysis tumors. Targeting metabolism (e.g., metformin, IDH inhibitors) is an active oncology field.
What inhibits the chain?
Cyanide blocks Complex IV — fatal in minutes. Carbon monoxide also Complex IV. Rotenone: Complex I (used as pesticide). Antimycin A: Complex III. Oligomycin: ATP synthase. Uncouplers (DNP, thermogenin in brown fat) collapse the gradient — heat instead of ATP. DNP was used for weight loss but caused hyperthermia and death.
What mitochondrial diseases exist?
Mitochondrial DNA mutations cause MELAS (encephalopathy, lactic acidosis, stroke-like episodes), MERRF (myoclonic epilepsy with ragged-red fibers), Leber's optic neuropathy, Kearns-Sayre. Inherited maternally because sperm mitochondria are degraded after fertilization. Heteroplasmy: cells contain mixture of normal and mutant mtDNA; symptoms appear above threshold (~70-90% mutant).