Q1 LONG ANSWER 10M ★ High-yield

Describe the components and organisation of the electron transport chain. Add a note on its inhibitors.

Biochemistry · 1st Professional — Pre-Clinical

Definition

Electron transport chain (respiratory chain) = a series of carriers in the inner mitochondrial membrane that transfer electrons from NADH and FADH2 to oxygen, releasing energy used to pump protons.

Feature	Detail
Site	Inner mitochondrial membrane
Purpose	Reoxidise NADH and FADH2 and create the proton gradient
Final acceptor	Molecular oxygen → water
Absent in	RBC (no mitochondria)
Accounts for	About 90% of all ATP produced

The inner membrane is impermeable to ions and rich in cardiolipin — both essential for holding the gradient
Its cristae greatly increase the surface area

The Four Complexes

Complex	Name	Prosthetic groups	Protons pumped
I	NADH–CoQ reductase	FMN, Fe–S centres	4 H+
II	Succinate–CoQ reductase	FAD, Fe–S	None
III	CoQ–cytochrome c reductase	Cytochromes b and c1, Fe–S	4 H+
IV	Cytochrome oxidase	Cytochromes a and a3, 2 copper centres	2 H+
V	ATP synthase	F0 and F1 subunits	Uses the gradient to make ATP

The two mobile carriers

Coenzyme Q (ubiquinone) — lipid-soluble, moves freely within the membrane; the only non-protein carrier; collects electrons from both complex I and complex II
Cytochrome c — a small water-soluble protein on the outer face of the inner membrane; carries one electron at a time

Sequence of Electron Flow

NADH → Complex I → Succinate (FADH2) → Complex II → Both feed into coenzyme Q → Complex III → cytochrome c → Complex IV → ½ O2 + 2H+ → H2O

Electrons flow down a redox gradient, from NAD+/NADH (−0.32 V) to O2/H2O (+0.82 V)
The total drop of 1.14 V releases about 52 kcal/mol — enough for roughly 3 ATP, of which about 40% is captured
FADH2 enters after complex I, bypassing one proton-pumping site — which is exactly why it yields 1.5 ATP against 2.5 for NADH

Other Substrates Entering at Coq

Glycerol-3-phosphate dehydrogenase — the glycerophosphate shuttle
Acyl-CoA dehydrogenase of β-oxidation, via ETF
Choline dehydrogenase
All are FAD-linked and therefore yield 1.5 ATP

Inhibitors

Site blocked	Inhibitor	Note
Complex I	Rotenone, amytal, piericidin, MPTP	Rotenone is an insecticide and fish poison; MPTP causes parkinsonism
Complex II	Malonate, carboxin	Competitive with succinate
Complex III	Antimycin A, BAL	—
Complex IV	Cyanide, carbon monoxide, azide, H2S	The most rapidly lethal
ATP synthase	Oligomycin	Blocks the F0 proton channel
ADP/ATP translocase	Atractyloside	Prevents ADP entering the matrix

CLINICAL PEARL

The consequence of any block is the same: electron flow stops, NADH accumulates, the proton gradient collapses and ATP synthesis ceases. Cells then depend entirely on glycolysis, producing lactic acidosis. Tissues with the highest demand — brain and heart — fail first.

Cyanide and Carbon Monoxide Poisoning

Cyanide binds the ferric iron of cytochrome a3 with very high affinity → histotoxic hypoxia: oxygen is delivered but cannot be used
Features — headache, confusion, seizures, bitter almond odour, and characteristically bright red venous blood with a high venous oxygen saturation, since the tissues extract none
Treatment — sodium nitrite to form methaemoglobin, which competes for cyanide; sodium thiosulphate to form thiocyanate; hydroxocobalamin to form cyanocobalamin; 100% oxygen
Carbon monoxide binds both haemoglobin and cytochrome oxidase; treated with 100% or hyperbaric oxygen

Iron–sulphur Proteins

Non-haem iron proteins in which iron is bound to cysteine sulphur and inorganic sulphide
Present in complexes I, II and III, and in aconitase
One-electron carriers, cycling between Fe3+ and Fe2+
Configurations — Fe2S2 and Fe4S4
Iron deficiency therefore impairs the chain before anaemia appears, contributing to fatigue and poor exercise tolerance

Applied Aspects

Mitochondrial diseases are maternally inherited and affect high-energy tissues — brain, heart, skeletal muscle, retina. Examples: melas, MERRF, Leber hereditary optic neuropathy, Leigh syndrome
Heteroplasmy — a cell contains both normal and mutant mitochondrial DNA; disease appears only above a threshold, which explains the variable severity
Ragged red fibres on muscle biopsy are the classical finding
Coenzyme Q10 deficiency is one of the few treatable mitochondrial disorders; statins may lower CoQ10 and contribute to myopathy
Reperfusion injury — restoring oxygen to ischaemic tissue floods a damaged chain with electrons, generating free radicals

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