Electron transport chain and oxidative phosphorylation

Last updated: January 24, 2023

Summary

Oxidative phosphorylation is a metabolic pathway through which cells release the energy stored in carbohydrates, fats, and proteins to produce adenosine triphosphate (ATP), the main source of energy for intracellular reactions. The process takes place within the mitochondria and involves oxidation-reduction reactions and the generation of an electrochemical gradient by the electron transport chain. The electron transport chain (mitochondrial respiratory chain) is embedded in the inner mitochondrial membrane and consists of four electron carrier complexes (complexes I–IV) that transfer electrons from nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂) to oxygen, thereby generating water (H₂O). The electron carrier complexes not only transfer electrons, but also pump protons out of the mitochondrial matrix into the mitochondrial intermembrane space, thereby creating an electrochemical gradient. Re-entry of these protons through ATP-synthase (complex V) into the mitochondrial matrix results in the phosphorylation of adenosine diphosphate (ADP) into ATP. Uncoupling agents, such as aspirin and 2,4-dinitrophenol, dissociate the electron transport chain from ATP synthesis by reducing the electrochemical gradient across the mitochondrial membrane. Oligomycin inhibits ATP synthesis by blocking the reflux of protons through ATP-synthase. In states of prolonged hypoxia (e.g., cardiac ischemia), the electron transport chain will stop running, ATP will no longer be produced, and cells may die.

ATP Synthase: Key Enzyme of Aerobic Energy Metabolism

Overview

Overview of ATP synthesis ^[1]

Sources of ATP synthesis

Sources of ATP synthesis and their caloric value
Source	Breakdown	Storage form	Characteristics	Caloric value (kcal/g)
Glucose	Via glycolysis	Stored as intracellular glycogen (released via glycogenolysis)	Short term reservoir of energy See “Carbohydrates”	4 kcal/g
Protein	Via glucose-alanine cycle Need to be converted to glucose in the liver via gluconeogenesis	Particularly stored in skeletal muscle	Important for muscle mass, wound healing, and intravascular oncotic pressure maintenance Only used during states of catabolism (e.g., fasting, cachexia) Daily protein requirements: 0.8–1.0 g/kg/day A nonprotein calorie:nitrogen ratio of 150:1 prevents protein catabolism for energy production See “Proteins and peptides”	4 kcal/g
Fat	Via β-oxidation	Stored as intracellular triglycerides within the muscle cells and adipose tissue	See “Lipids and fat metabolism”	9 kcal/g
Ketone bodies	Via ketogenolysis	Usually not stored Constantly produced in small amounts by the liver	Main energy source when glucose is not readily available (e.g., fasting, diabetic ketoacidosis) See “Ketone body metabolism”	∼ 4 kcal/g ^[2]

Pathways of ATP synthesis

Storage of ATP is very limited and requires constant reproduction.
The mechanism by which ATP is produced depends on the type of activity (i.e., the energy demand) and the oxygen supply.

ATP synthesis
Type of metabolism	Type of activity	Pathway
Aerobic metabolism	Resting and nonstrenuous exercise states (e.g., walking)	Main sources Glucose (via glycolysis) Fatty acids (via β-oxidation) TCA cycle, and oxidative phosphorylation via the electron transport chain Requires O₂ and produces CO₂ and water
Anaerobic metabolism	Sustained strenuous exercise	Anaerobic glycolysis: glucose → pyruvate → lactic acid + 2 ATP Lactic acid cycle Lactate cannot be metabolized by muscle cells Lactate is transported to the liver → LDH converts lactate into pyruvate → pyruvate is converted into glucose → glucose is transported to muscle cells Occurs in the absence of oxygen In skeletal muscle, brain, RBCs, WBCs, kidney medulla, lens, testes, and cornea
Anaerobic metabolism	Sudden, short bursts of rapid movement	Immediate resynthesis of ATP from ADP (very limited supply) Creatine kinase reaction Adenylate kinase reaction Occurs in the absence of oxygen
Protein metabolism	During states of catabolism (e.g., fasting, cachexia)	Glucose-alanine cycle: proteins need to be converted to glucose in the liver via gluconeogenesis Protein degradation → transamination of pyruvate to alanine by ALT in muscle cells → alanine transported to the liver → alanine transaminated to pyruvate by ALT → gluconeogenesis converts pyruvate to glucose

Chalk Talk: Energy Metabolism - Part 8 Metabolic fuel usage Energy metabolism in a muscle cell Lactic acid cycle and alanine cycle in skeletal muscle and liver

Overview of oxidative phosphorylation and the electron transport chain

Oxidative phosphorylation and the electron transport chain
	Electron transport chain	Oxidative phosphorylation
Definition	An electron transport chain composed of a series of four membrane-bound protein complexes (complexes I–IV) that catalyze redox reactions to power ATP synthesis	Creation of an electrochemical proton gradient over the inner mitochondrial membrane, which powers oxidative phosphorylation
Function	The process of coupling the electron transport chain with ATP synthesis, catalyzed by ATP-synthase (complex V)	Production of ATP, which provides energy for intracellular reactions
ATP produced	One glucose molecule yields 32 net ATP (via aerobic metabolism) through the malate-aspartate shuttle, which is mainly found in heart and liver tissue. One glucose molecule yields 30 net ATP (via aerobic metabolism) through the glycerol-3-phosphate shuttle, which is mainly found in muscle tissue.

Mitochondrion Chalk Talk: Energy Metabolism - Part 7

Overview of the phosphagen system ^[3]

Storage of ATP within muscle cells is very limited.
Phosphagens (e.g., phosphocreatine)
- Compounds with high-energy phosphate reserves
- Provides a phosphate pool to enable rapid regeneration of ATP during short periods of high energy demand
Phosphagen system: utilizes phosphagens to create an immediate but limited supply of ATP during short bursts of strenuous movement (e.g., start of a sprint, powerlifting)
- Creatine kinase reaction
- Adenylate kinase reaction

Phosphagen reactions
	Adenylate kinase reaction	Creatine kinase reaction
Location of enzyme	Mitochondrial intramembrane space	Skeletal muscle, cardiac muscle, and brain
Transfer of phosphate	Transfers a phosphate residue from one ADP to another to create ATP ADP + ADP ⇄ ATP + AMP	Transfer of phosphate between phosphocreatine and ADP Phosphocreatine + ADP ⇄ creatine + ATP

ATP and phosphocreatine are both important short-term energy stores in muscle cells. Creatine metabolism

Electron transport chain and ATP synthesis

Electron donors of the electron transport chain
- NADH (from glycolysis) is transferred into the mitochondrial matrix via the malate-aspartate shuttle or glycerol-3-phosphate shuttle
- FADH₂ is produced by succinate dehydrogenase in the TCA cycle
Protein complexes: located within the inner mitochondrial membrane
- The electrons from NADH and FADH₂ move along specific complexes of the electron transport chain via redox reactions until they are transferred to oxygen.
- NADH enters the electron transport chain at complex I, whereas FADH enters at complex II; . Therefore, NADH promotes the passage of more protons across the electron transport chain and yields more ATP compared to FADH₂.

Protein complexes of electron transport chain and oxidative phosphorylation
	Reactions	Equation
Electron transport chain
Complex I (NADH dehydrogenase)	Transfers two protons (H⁺) and two electrons (e^-) to coenzyme Q Pumps four protons into the intermembrane space	NADH → NAD⁺ + H⁺ + 2 e^-
Complex II (contains succinate dehydrogenase )	Transfers two protons (H⁺) and two electrons (e^-) to coenzyme Q Does not pump protons into the intermembrane space	FADH₂ → FAD + 2 H⁺ + 2 e^-
Complex III (coenzyme Q-cytochrome c reductase)	Transfers two electrons (e^-) from coenzyme Q to two molecules cytochrome c Transfers 4 protons (H⁺) into the intermembrane space	Reduced coenzyme Q (QH₂) + 2 H⁺ + 2 oxidized cytochrome c → oxidized coenzyme Q + 4 H⁺ + 2 reduced cytochrome c
Complex IV (cytochrome c oxidase)	Reduces oxygen (O₂) to water (H₂O) via cytochrome a/a₃ (Cu/heme protein) Pumps two protons (H⁺) into the intermembrane space The transfer of electrons powers the transport of protons across the inner mitochondrial membrane into the intermembrane space → creates an electrochemical gradient across the inner mitochondrial membrane → powers the ATP synthase Transfer of 4 H⁺ back into the mitochondrial matrix through ATP synthase (complex V) → phosphorylation of 1 adenosine diphosphate (ADP) → 1 adenosine triphosphate (ATP)	2 reduced cytochrome c + ½ O₂ + 4 H⁺ → 2 oxidized cytochrome c + H₂O + 2 H⁺
Oxidative phosphorylation
Complex V (ATP synthase)	Acts as proton channel, works like a turbine → flow of protons allows generation of ATP For every 4 protons, one ATP is generated	ADP + Pi → ATP Yield 1 NADH → transport of 10 H⁺→ 2.5 ATP 1 FADH₂ → transport of 6 H⁺→ 1.5 ATP

NAD+ / NADH redox pair FAD / FADH2 redox pair Respiratory chain Structure of ATP synthase ATP Synthase: Key Enzyme of Aerobic Energy Metabolism Physeo - Electron Transport Chain

Clinical significance

Uncoupling agents: dissociation of the electron transport chain and ATP synthase
- Increased permeability of mitochondrial membrane → reduced proton gradient and increased oxygen consumption → electron transfer continues but ATP synthesis stops → production of heat
  - Salicylic acid (in high dosages; fever commonly develops after overdose)
  - 2,4-Dinitrophenol
  - Thermogenin (in brown fat, which contains more mitochondria than white fat): a proton channel that physiologically uncouples electron transport and ATP synthesis to generate heat
Respiratory chain inhibitors
- Electron transport chain inhibitors
  - Poisons that disrupt oxidative phosphorylation:
    - Rotenone: inhibits complex I
    - Antimycin: inhibits complex III
    - Cyanide, carbon monoxide, azides: inhibit complex IV
- ATP synthase inhibitors: block ATP synthesis by stopping the electron transfer via an increased proton gradient (e.g., oligomycin)
Prolonged tissue hypoxia (e.g., in myocardial infarction): lack of O2 molecules to accept the electrons NADH and FADH₂ → disruption of the electron transport chain → decreased ATP production → cell injury or death

To remember complex 1 (rotenone) and 3 (antimycin) inhibitors, think: “one rotten carrot, three antsy (anti) mice.”

Mechanism of action: respiratory chain inhibitors

References

Feher JJ. Quantitative Human Physiology. Academic Press ; 2017
Reichard GA Jr, Owen OE, Haff AC, Paul P, Bortz WM. Ketone-body production and oxidation in fasting obese humans.. J Clin Invest. 1974; 53 (2): p.508-15.doi: 10.1172/JCI107584 . | Open in Read by QxMD
Baker JS, McCormick MC, Robergs RA. Interaction among Skeletal Muscle Metabolic Energy Systems during Intense Exercise.. J Nutr Metab. 2010; 2010: p.905612.doi: 10.1155/2010/905612 . | Open in Read by QxMD
Kaplan. USMLE Step 1 Lecture Notes 2018: Biochemistry and Medical Genetics. Kaplan ; 2017
Chatterjea M, Shinde R. Textbook of Medical Biochemistry. JP Medical Ltd ; 2011

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