Glycolysis, PDH, TCA, and the ETC are not isolated pathways. They are tightly coordinated so that fuel oxidation matches ATP demand. Understanding how they interconnect is how the MCAT asks you to think about metabolism as a whole.
Glucose-6-phosphateThe first fork. G6P can be stored as glycogen, burned through glycolysis, or diverted to the pentose phosphate pathway for NADPH and ribose-5-P. It cannot leave the cell: only liver and kidney have glucose-6-phosphatase to turn it back into free glucose.
PyruvateThe last cytosolic fork. With oxygen it crosses into the mitochondrion for PDH; without oxygen it becomes lactate; in muscle it is transaminated to alanine; and in the fasting liver it is carboxylated to oxaloacetate to start gluconeogenesis.
Acetyl-CoAThe great convergence: carbohydrate, fat, and ketogenic amino acids all arrive here. It burns in the TCA cycle, leaves as citrate for fatty acid and cholesterol synthesis, or condenses into ketone bodies. It can never become glucose, which is why fat is not a gluconeogenic fuel.
OxaloacetateGatekeeper of the TCA cycle and the doorway out of it. Acetyl-CoA cannot enter the cycle without OAA, so when OAA is drained for gluconeogenesis during fasting, acetyl-CoA backs up and is shunted into ketone bodies. OAA also trades with the urea cycle as aspartate and fumarate.
Read it top to bottom for catabolism, bottom to top for anabolism. Fuels enter at the top, carbon funnels through four junction metabolites, and the electron carriers cash out at the electron transport chain. The four navy pills are the only molecules you need to reason from: know what enters and leaves each one and you can rebuild the rest of the map from memory.
Each arrow is a regulatory checkpoint. The overall rate is set by the slowest committed step of the entire chain.
Respiratory Control
In isolated mitochondria, the rate of O2 consumption depends on ADP availability. When ADP is low (cell has plenty of ATP), ATP synthase cannot run; the PMF builds up; the ETC cannot pump more protons; NADH accumulates; TCA and PDH slow; glycolysis slows. When ADP rises (ATP being consumed), the whole chain speeds up in synchrony.
This is respiratory control: the rate of fuel oxidation = the rate of ATP consumption. The cell never oxidizes fuel faster than it uses ATP.
The Pasteur Effect
Louis Pasteur observed that yeast glucose consumption slows dramatically when oxygen is added. Anaerobic glycolysis burns glucose fast (2 ATP per glucose). Aerobic respiration is 15x more efficient (30-32 ATP per glucose), so less glucose is needed. Adding O2 raises ATP, which inhibits PFK-1, slowing glycolysis. The Pasteur effect is the textbook name for this regulatory coupling.
Cancer and the Warburg Effect
Many cancer cells show the opposite - they rely heavily on glycolysis even in the presence of O2 (aerobic glycolysis), producing lactate as their main end product. This is the Warburg effect. Reasons are complex but likely include mitochondrial dysfunction, enhanced biosynthesis, and rapid growth requirements. PET scans exploit the Warburg effect: radioactive glucose analogs (FDG) accumulate in cancer cells because of their high glucose uptake.
What is respiratory control?
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The coupling of fuel oxidation rate to ATP consumption rate. ADP availability ultimately sets the rate - when ADP is low (ATP high), ATP synthase cannot run, the proton gradient backs up, the ETC slows, NADH accumulates, TCA and PDH slow, and glycolysis slows. When ADP rises (ATP being used), the entire chain speeds up in synchrony. The cell never oxidizes fuel faster than it needs ATP.
What is the Pasteur effect?
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When oxygen is added to a culture, glucose consumption slows dramatically. Because aerobic respiration yields ~15x more ATP per glucose than anaerobic glycolysis, far less glucose is needed to meet the same ATP demand. The added ATP inhibits PFK-1, slowing glycolysis. Observed by Pasteur in fermenting yeast, this is a textbook example of metabolic regulation coupling.
What is the Warburg effect, and why is it exploited in PET imaging?
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Many cancer cells rely heavily on aerobic glycolysis (converting pyruvate to lactate even with O2 present) instead of oxidative phosphorylation. The Warburg effect results in high glucose uptake by tumors. PET scans use fluorodeoxyglucose (FDG), a radioactive glucose analog. Tumors take up FDG at elevated rates and become visible on PET, enabling non-invasive cancer imaging.
