STEPTRACKERBIOCHEMISTRY + TOXICOLOGY | CARBOHYDRATE METABOLISM | HIGH-YIELD REVIEW

TCA Cycle & Electron Transport

Acetyl-CoA is burned to CO₂, its electrons ride NADH and FADH₂ down the chain, and the proton gradient spins ATP synthase — know each poison's address.

FOCUS ON

TCA: "Can I Keep Selling Sex For Money, Officer?" — citrate, isocitrate, α-KG, succinyl-CoA, succinate, fumarate, malate, OAA. Per acetyl-CoA: 3 NADH, 1 FADH₂, 1 GTP, 2 CO₂. Rate-limiting: isocitrate DH. ETC: complex I (rotenone), III (antimycin A), IV (cyanide, CO, H₂S, azide), V ATP synthase (oligomycin). Uncouplers (2,4-DNP, aspirin overdose, thermogenin) → heat, no ATP.

STEP · COMPLEX

WHAT IT DOES

PRODUCT · REGULATION

POISON · CLUE

Citrate synthase

Acetyl-CoA + OAA → citrate

Inhibited by ATP, NADH, citrate, succinyl-CoA

Citrate exported for fatty acid synthesis

Isocitrate dehydrogenase

rate-limiting

Isocitrate → α-KG + CO₂

NADH · + ADP · − ATP, NADH

IDH1/2 mutations in gliomas, AML (2-hydroxyglutarate)

α-Ketoglutarate dehydrogenase

α-KG → succinyl-CoA + CO₂

NADH · same 5 cofactors as PDH

Arsenite, thiamine deficiency

Succinyl-CoA synthetase

Succinyl-CoA → succinate

GTP (substrate-level)

Succinyl-CoA also starts heme synthesis

Succinate dehydrogenase

= complex II

Succinate → fumarate

FADH₂ (feeds ETC directly)

SDH mutations → paraganglioma/pheochromocytoma

Fumarase → malate DH

Fumarate → malate → OAA

NADH

Fumarate hydratase loss → leiomyomas + RCC

Complex I

NADH → ubiquinone; pumps H⁺

—

Rotenone, metformin (weak)

Complex III

Ubiquinol → cytochrome c; pumps H⁺

—

Antimycin A

Complex IV

Cytochrome c → O₂ (→ H₂O); pumps H⁺

—

Cyanide, CO, H₂S, azide — tissue hypoxia with normal PaO₂

Complex V — ATP synthase

H⁺ flow back into matrix drives ATP synthesis

~2.5 ATP per NADH, ~1.5 per FADH₂

Oligomycin (↓ O₂ use, ↑ gradient)

Uncouplers

Let H⁺ leak across the inner membrane without ATP synthase

O₂ use ↑, ATP ↓, heat ↑

2,4-dinitrophenol (diet pills), salicylate overdose, thermogenin (brown fat)

Picture it — electron transport chain and its poisons

Inner mitochondrial membraneNADH enters at complex I, FADH₂ at complex II; electrons pass via CoQ and cytochrome c to complex IV and O₂. Complexes I, III and IV pump H⁺; the gradient drives ATP synthase (V). Red = inhibitor at each site; uncouplers let H⁺ leak back without making ATP.

Schematic diagrams, not to scale.

Mechanism — electrons downhill, protons uphill

NADH → Complex IFADH₂ → Complex II

→

CoQ → Complex III

→

Cytochrome c → Complex IVO₂ → H₂O

→

H⁺ gradient

→

ATP synthaseADP → ATP

Inhibitors of I–IV and of ATP synthase both stop O₂ use. Uncouplers raise O₂ use while ATP falls.

Poisons compared

CLASS

EXAMPLE

O₂ USE

GRADIENT

ETC inhibitor

Cyanide, CO, rotenone

↓

ATP synthase inhibitor

Oligomycin

↓

↑

Uncoupler

2,4-DNP, aspirin

↑

↓

How it's tested

COMMON CONFUSIONCyanide poisoning gives bright red venous blood (tissues can't extract O₂) and lactic acidosis with a normal PaO₂; CO also impairs O₂ carriage (↓ O₂ content).

THE TRAPHyperthermia in salicylate overdose comes from uncoupling — more O₂ consumed, energy lost as heat.

YOUR APPROACHLocate the block (TCA step or complex) → effect on O₂ use and gradient → antidote (hydroxocobalamin, nitrites/thiosulfate, 100% O₂).

If you see… think…

Rate-limiting TCA enzyme → isocitrate dehydrogenase

Products per acetyl-CoA → 3 NADH, 1 FADH₂, 1 GTP, 2 CO₂

TCA enzyme that is also part of the ETC → succinate DH (complex II)

House fire victim, almond breath, lactic acidosis → cyanide (complex IV)

Cyanide antidote → hydroxocobalamin (or nitrites + thiosulfate)

Weight-loss pill causing hyperthermia → 2,4-dinitrophenol (uncoupler)

Brown fat heat production → thermogenin (UCP1)

Pesticide blocking complex I → rotenone

Inhibitor of ATP synthase → oligomycin

Glioma mutation making 2-hydroxyglutarate → IDH1/2