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Electron Transport
Chain
Jason Ryan, MD, MPH
Electron Transport Chain

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NADH
FADH2

Blausen gallery 2014". Wikiversity Journal of Medicine

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Aerobic Metabolism
Cytosol Mitochondria
GTP
NADH
NADH
2 ATP Acetyl CoA ATP
NADH
Pyruvate FADH2
Glucose
Pyruvate NADH
NADH
2 NADH Acetyl CoA ATP
NADH
FADH2
GTP
Malate Shuttle

Aspartate OAA Malate

α-KG Glut NADH NAD+ Cytosol

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Mitochondria
Aspartate OAA Malate

α-KG NADH NAD+

Glut
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Glycerol Phosphate Shuttle

Glycerol
Phosphate
Dehydrogenase
Dihydroxyacetone Glycerol
phosphate Phosphate

NADH NAD+

Cytosol
Glycerol
Glycerol
Phosphate
Phosphate
Dehydrogenas
Dehydrogenase
e
Mitochondria
FAD FADH2
Electron Transport
• Extract electrons from NADH/FADH2
• Transfer to oxygen (aerobic respiration)
• In process, generate/capture energy
• NADH → NAD+ + H+ + 2e-
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• FADH2 → FAD + 2 H + 2e-
+

• 2e- + 2H+ + ½O2 → H2O

Blausen gallery 2014". Wikiversity Journal of Medicine

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Electron Transport Complexes

Cytosol

Outer
Membrane

Inter
Membrane
Space

Inner
I II III IV Membrane
Complex I
• NADH Dehydrogenase
• Oxidizes NADH (NADH → NAD+)
• Transfers electrons to coenzyme Q (ubiquinone)

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e-

NADH CoQ
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Complex I
• CoQ shuttles electrons to complex III
• Pumps H+ into intermembrane space
• Key intermediates:
• Flavin mononucleotide (FMN)
• Iron sulfur compounds (FeS)

e- e- e-

NADH FMN FeS CoQ

 Electron Transport
Cytosol

Outer
Membrane

Inter
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Membrane H+
e- e-
Space

CoQ Inner
I III Membrane

H+
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CoQ 10 Supplements
• Some data indicate statins decrease CoQ levels
• Hypothesized to contribute to statin myopathy
• CoQ 10 supplements may help in theory
• No good data to support this use

Ragesoss/Wikipedia
Complex II
• Succinate dehydrogenase (TCA cycle)
• Electrons from succinate → FADH2 → CoQ

FAD
Succinate AfraTafreeh.com

II
FADH2 CoQ
Fumarate Succinate
Dehydrogenase
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Complex III
• Cytochrome bc1 complex
• Transfers electrons CoQ → cytochrome c
• Pumps H+ to intermembrane space
 Electron Transport
Cytosol

Outer
Membrane

Inter
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Membrane H+ e- Cyt c e-
Space

Inner
III IV Membrane

H+
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Cytochromes
• Class of proteins
• Contains a heme group
• Iron plus porphyrin ring
• Hgb: mostly Fe2+
• Cytochromes: Fe2+ → Fe3+
• Oxidation state changes with electron transport
• Electron transport: a, b, c
• Cytochrome P450: drug metabolism
Complex IV
• Cytochrome a + a3
• Cytochrome c oxidase (reacts with oxygen)
• Contains copper (Cu)
• Electrons and O2 → H2O
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• Also pumps H+
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Electron Transport
Cytosol

Outer
Membrane

Inter H+ H+ H+ H+
Membrane H+
H+ H +H+ H+ H H
+ H+
+ H+
H+
H+ H+H+
H+ + H H+
+
Space HH+ + H + H+ + H+
H
H +
H + H+H H +
H + H +
H + H + H +
H+ H+ H+
H+
H +

CoQ
Cyt c Inner
I II III IV Membrane

O2 H2O
Phosphorylation
• Two ways to produce ATP:
• Substrate level phosphorylation
• Oxidative phosphorylation
• Substrate level phosphorylation (via enzyme):
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Phosphoenolpyruvate
ADP

ATP
Pyruvate
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Oxidative Phosphorylation
Cytosol

Outer
Membrane

Inter H+ H+ H+ H+ H+ H+
H+
Membrane H+ H+ H+ H+ H +
+
+ H+
H+ H+ H+ H+ H H+ H
Space

Inner
ATP
Membrane
Synthase

ADP ATP
ATP Synthase
• Complex V
• Converts proton (charge) gradient → ATP
• “electrochemical gradient”
• “proton motive force”
• Protons move down gradient (“chemiosmosis”)
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P/O Ratio
• ATP per molecule O2
• Classically had to be an integer
• 3 per NADH
• 2 per FADH2
• Newer estimates
• 2.5 per NADH
• 1.5 per FADH2

Hinkle P. P/O ratios of mitochondrial oxidative phosphorylation.

Biochimica et Biophysica Act 1706 (Jan 2005) 1-11
 Aerobic Energy Production
30/32 ATP Cytosol Mitochondria
per glucose GTP (1ATP)
NADH
NADH
2 ATP Acetyl CoA 9 ATP
NADH
AfraTafreeh.com FADH
Pyruvate NADH (2.5) 2
Glucose
Pyruvate NADH (2.5) NADH
NADH
2 NADH Acetyl CoA 9 ATP
NADH
Malate 2 NADH (5) FADH2

2 FADH2 (3) GTP (1 ATP)

Glycerol-3-P
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Drugs and Poisons

• Two ways to disrupt oxidative phosphorylation
• #1: Block/inhibit electron transport
• #2: Allow H+ to leak out of inner membrane space
• “Uncoupling” of electron transport/oxidative phosphorylation
Inhibitors
• Rotenone (insecticide)
• Binds complex I
• Prevents electron transfer (reduction) to CoQ
• Antimycin A (antibiotic)
• Complex III (bc1 complex)
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• Complex IV
• Carbon monoxide (binds a3 in Fe2+ state – competes with O2)
• Cyanide (binds a3 in Fe3+ state)
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Cyanide Poisoning
• CNS: Headache, confusion
• Cardiovascular: Initial tachycardia, hypertension
• Respiratory: Initial tachypnea
• Bright red venous blood: ↑O2 content
• Almond smell
• Anaerobic metabolism: lactic acidosis

Mullookkaaran/Wikipedia
Cyanide Poisoning
• Nitroprusside: treatment of hypertensive
emergencies
• Contains five cyanide groups per molecule
• Toxic levels with prolonged infusions
• Treatment: Nitrites (amyl nitrite)
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• Converts Fe2+ → Fe3+ in Hgb (methemoglobin)
• Fe3+ in Hgb binds cyanide, protects mitochondria
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Uncoupling Agents
Cytosol

Outer
Membrane

Inter H+ H+ H+ H+ H+ H+
H+
Membrane H+ H+ H+ H+ H +
+
+ H+
H+ H+ H+ H+ H H+ H
Space

Inner
ATP
Membrane
Synthase

ADP ATP
Uncoupling Agents
• 2,4 dinitrophenol (DNP)
• Aspirin (overdose)
• Brown fat
• Newborns (also hibernating animals)
• Uncoupling protein 1 AfraTafreeh.com
(UCP-1, thermogenin)
• Sympathetic stimulation (NE, β receptors) → lipolysis
• Electron transport → heat (not ATP)

All lead to production of heat

Pixabay/Public Domain
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Oligomycin A
• Macrolide antibiotic
• Inhibits ATP synthase
• Protons cannot move through enzyme
• Protons trapped in intermembrane space
• Oxidative phosphorylation stops
• ATP cannot be generated