Electron transport chain Biochemistry

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Electron Transport Chain (ETC)

Biochemistry, 8th ed Lippincott Illustrated Reviews | Basic Medical Biochemistry - A Clinical Approach, 6e

Overview

Energy-rich molecules (glucose, fatty acids, amino acids) are oxidized through a series of reactions that ultimately produce CO2 and H2O. During these processes, metabolic intermediates donate electrons to two coenzymes - NAD+ and FAD - forming the energy-rich reduced forms NADH and FADH2. These then donate electron pairs to the ETC.

The ETC is located in the inner mitochondrial membrane (IMM), with the exception of cytochrome c (which is mobile in the intermembrane space). It is the final common pathway by which electrons derived from all fuels flow to oxygen, reducing it to H2O. The coupling of electron transport with ATP synthesis is called oxidative phosphorylation (OXPHOS).

Mitochondrial Structure

Compartment	Features
Outer membrane	Contains porin channels - freely permeable to small ions and molecules
Inner membrane	Impermeable to H+, ATP, ADP, pyruvate - requires specific transporters; rich in cristae (increases surface area); over half of its proteins are involved in OXPHOS
Intermembrane space	Where H+ accumulates during electron transport
Matrix	Contains TCA cycle enzymes, β-oxidation enzymes, NAD+, FAD, ADP, Pi

The Four Complexes

Here is the overall ETC diagram from Basic Medical Biochemistry, 6e:

Complex I - NADH Dehydrogenase (NADH:CoQ Oxidoreductase)

Accepts electrons from: NADH
Electron path: NADH → FMN (flavin mononucleotide) → Fe-S centers → CoQ
Protons pumped: 4 H+ from matrix to intermembrane space
FMN is a coenzyme derived from riboflavin (vitamin B2)
Contains multiple Fe-S center subunits

Complex II - Succinate Dehydrogenase

Accepts electrons from: FADH2 (produced by oxidation of succinate to fumarate in the TCA cycle)
Electron path: FADH2 → Fe-S protein → CoQ
Protons pumped: 0 - no proton pumping occurs at this complex because no energy is lost in this step
Also accepts electrons from glycerol 3-phosphate dehydrogenase, acyl CoA dehydrogenase (fatty acid oxidation), and ETF:CoQ oxidoreductase - all feed into CoQ without proton pumping

Coenzyme Q (CoQ / Ubiquinone)

A lipid-soluble quinone with a long hydrophobic isoprenoid tail (made from a cholesterol synthesis intermediate)
Acts as a mobile electron carrier, collecting electrons from Complexes I and II and passing them to Complex III
Serves as a junction point linking flavoprotein dehydrogenases to cytochromes
When it accepts electrons (becomes reduced to CoQH2), it picks up protons from the matrix side

Complex III - Cytochrome bc1 Complex (Cytochrome b-c1)

Accepts electrons from: CoQH2
Electron path: CoQ → Cyt b → Fe-S → Cyt c1 → Cytochrome c
Protons pumped: 4 H+ to intermembrane space
Transfers electrons one at a time to the mobile carrier cytochrome c

Cytochrome c

A small cytochrome protein in the intermembrane space
Mobile carrier that shuttles single electrons between Complex III and Complex IV
Clinically important: its release from mitochondria into the cytosol triggers apoptosis (stimulates apoptosome formation and caspase activation)

Complex IV - Cytochrome c Oxidase (Cytochrome a + a3)

Accepts electrons from: Cytochrome c
Electron path: CuA → Cyt a → Cyt a3 (with CuB) → O2
Terminal reaction: 4e- + 4H+ + O2 → 2 H2O
Protons pumped: 2 H+ to intermembrane space
This is the only electron carrier where the heme iron can directly react with O2
Contains copper (Cu) atoms essential for this reaction
Also called "cytochrome c oxidase" - the only complex where O2 binds

Proton Pumping Summary

Complex	Enzyme	H+ pumped (per NADH)	Electrons from
I	NADH dehydrogenase	4 H+	NADH
II	Succinate dehydrogenase	0	FADH2
III	Cytochrome bc1	4 H+	CoQ
IV	Cytochrome c oxidase	2 H+	Cyt c
Total		10 H+ per NADH

(For FADH2, Complex I is bypassed, so only 6 H+ are pumped - via Complexes III and IV)

ATP Synthesis - Chemiosmotic Hypothesis (Mitchell Hypothesis)

The pumping of H+ creates two gradients across the IMM:

Chemical gradient (pH gradient) - cytosolic side is more acidic
Electrical gradient - cytosolic side is more positively charged

Together these form the proton-motive force (Δp), which drives ATP synthesis.

Complex V - ATP Synthase (F1F0-ATPase)

F0 domain - spans the IMM; contains a c-ring H+ channel (8 c subunits in vertebrates); binding target of oligomycin
F1 domain - protrudes into the matrix; contains 3 β subunits that synthesize ATP; can also hydrolyze ATP (hence "ATPase")
H+ re-entering the matrix through F0 drive rotation of the c ring
This rotation causes conformational changes in F1 β subunits: bind ADP+Pi → phosphorylate ADP → release ATP
One full rotation = 3 ATP produced
8 H+ required to drive one full rotation (so ~2.7 H+ per ATP; P:O ≈ 2.5 for NADH, 1.5 for FADH2)

ATP Yield

Substrate	ATP produced (current estimates)
1 NADH	~2.5 ATP
1 FADH2	~1.5 ATP
1 glucose (complete oxidation)	~30-32 ATP
1 pyruvate (complete oxidation)	~12.5 ATP

The 30-32 ATP per glucose depends on which cytosolic NADH shuttle is used:

Malate-aspartate shuttle - produces NADH in matrix → ~2.5 ATP per cytosolic NADH (more efficient, in liver, heart)
Glycerol 3-phosphate shuttle - produces FADH2 in matrix → ~1.5 ATP per cytosolic NADH (in muscle, brain)

Inhibitors of the ETC

Site	Inhibitor	Mechanism
Complex I	Rotenone, amytal (amobarbital), metformin	Block NADH → CoQ electron transfer
Complex II	Malonate	Competitive inhibitor of succinate dehydrogenase
Complex III	Antimycin A	Blocks CoQ → Cyt c electron transfer
Complex IV	Cyanide (CN-), CO, azide, H2S	Bind Fe in Cyt a3; block O2 reduction
Complex V (ATP synthase)	Oligomycin	Blocks H+ channel in F0; stops ATP synthesis

Key point: Inhibition at any point in the chain causes all carriers upstream (before the block) to become fully reduced, while those downstream become fully oxidized. Because electron transport and phosphorylation are tightly coupled, blocking the chain also stops ATP synthesis - and vice versa (oligomycin blocks ATP synthesis which backs up H+ gradient, which halts electron transport).

Uncouplers

Uncouplers dissipate the H+ gradient without generating ATP, so the energy is released as heat instead. The ETC actually speeds up (to try to restore the gradient), but no ATP is made.

Uncoupler	Notes
2,4-Dinitrophenol (DNP)	Synthetic; lipid-soluble proton carrier; was used (dangerously) as a weight-loss drug in the 1930s
Aspirin (high doses)	Can uncouple mitochondria
UCP1 (thermogenin)	Physiological uncoupler in brown adipose tissue; responsible for non-shivering thermogenesis in neonates and cold-acclimatized individuals

Reactive Oxygen Species (ROS)

Electron leakage from the ETC (particularly at Complexes I and III) generates ROS:

Superoxide (O2-) → Hydrogen peroxide (H2O2) → Hydroxyl radical (·OH)

Cellular defenses:

Superoxide dismutase (SOD) converts O2- to H2O2
Catalase converts H2O2 to H2O + O2
Glutathione peroxidase reduces H2O2 using glutathione

Mitochondrial Disease (OXPHOS Disorders)

13 of ~90 ETC polypeptides are encoded by mitochondrial DNA (mtDNA); the rest are nuclear-encoded
mtDNA mutation rate is ~10× that of nuclear DNA
mtDNA is maternally inherited (sperm mitochondria are eliminated at fertilization)
High-energy tissues are most vulnerable: brain, nerves, retina, skeletal muscle, heart, liver

Disease	Key Features
Kearns-Sayre syndrome	Ptosis, ophthalmoplegia, cardiac conduction defects, ataxia, myopathy; onset before age 20; mtDNA deletion
Leber hereditary optic neuropathy (LHON)	Bilateral central vision loss; onset 20s-30s
MELAS	Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes
MERRF	Myoclonic epilepsy, ragged-red fibers on muscle biopsy
General features	Lactic acidosis, seizures, ophthalmoplegia, myopathy, cardiomyopathy

Quick Memory Aid - ETC Flow

NADH → Complex I → CoQ → Complex III → Cyt c → Complex IV → O2 → H2O
                  ↑
FADH2 → Complex II ┘
         (no H+ pump)
                              ↓ H+ gradient drives ↓
                         Complex V (ATP synthase)
                              ADP + Pi → ATP

Complexes that pump H+: I (4), III (4), IV (2) - "1, 3, 4 pump; 2 does not"

Sources: Biochemistry, 8th ed Lippincott Illustrated Reviews, pp. 224-252 | Basic Medical Biochemistry - A Clinical Approach, 6e, Chapter 24

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