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.
Overview of ATP synthesis 
Sources of ATP synthesis
|Sources of ATP synthesis and their caloric value|
|Source||Breakdown||Storage form||Characteristics||Caloric value (kcal/g)|
|Glucose|| || || || |
|Protein|| || |
|Fat|| || |
| || || |
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.
|Type of metabolism||Type of activity||Pathway|
|Aerobic metabolism|| |
|Anaerobic metabolism|| || |
Overview of oxidative phosphorylation and the electron transport chain
|Oxidative phosphorylation and the electron transport chain|
|Electron transport chain||Oxidative phosphorylation|
Overview of the phosphagen system 
- Storage of ATP within muscle cells is very limited.
- (e.g., )
- 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)
|Adenylate kinase reaction||Creatine kinase reaction|
|Location of enzyme|| |
|Transfer of phosphate|
ATP and phosphocreatine are both important short-term energy stores in muscle cells.
- Electron donors of the electron transport chain
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|
|Electron transport chain|
|Complex I (NADH dehydrogenase)|| |
|(contains )|| |
|Complex III (coenzyme Q-cytochrome c reductase)|| |
|Complex IV (cytochrome c oxidase)|| |
|Complex V (ATP synthase)|
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
Respiratory chain inhibitors
- Electron transport chain inhibitors
- ATP synthase inhibitors: block ATP synthesis by stopping the electron transfer via an increased proton gradient (e.g., oligomycin)
- Prolonged tissue (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