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Biological and Biochemical Foundations of Living Systems

Oxidative Phosphorylation

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Electron transport chain (ETC) and oxidative phosphorylation, substrates and products, general features of the pathway

The electron transport chain harnesses energy released from oxidation of reduced electron carriers (NADH, FADH2) to drive phosphorylation (ATP synthesis).

Substrates of the ETC include NADH and FADH2, which donate their electrons to a series of proteins embedded in the inner membrane of the mitochondria separating the matrix (location of citric acid cycle) and the intermembrane space (location for buildup of proton gradient), and the final electron acceptor O2 along with hydrogen protons that are used in reduction of oxygen (4 H+ + O2 → 2 H2O) and transported to build a proton gradient across the inner membrane.

The products of the ETC thus are the oxidized NAD+ and FAD forms of the soluble electron carriers, H2O, and ATP produced from harnessing the energy of protons returning to the mitochondrial matrix down the inner membrane proton gradient.

Electron transfer in mitochondria

As electrons are passed through the chain of proteins in the ETC, protons are pumped across the inner membrane building a proton gradient in the intermembrane space of the mitochondria. This chain of proteins form four complexes with Coenzyme Q, soluble within the lipid membrane, assisting in transporting electrons from Complex II to Complex III.


NADH interacts at the first protein complex of the ETC, donating its electron (along with its hydrogen), contributing to the proton gradient at this stage and at later stages as the passed electrons aid in pumping additional protons at the third and fourth complexes.

Oxidative activity of the ETC produces a degree of reactive oxygen species with the potential for causing oxidative damage. NADPH, which has a role in the Pentose Phosphate Pathway, does not play a direct role in oxidative phosphorylation coupled to the ETC, but does have a capacity to neutralizing reactive oxygen species.


Flavoproteins are a class of proteins that contain flavin (a nucleic acid derivative of riboflavin [vitamin B2]) and can assist in redox reactions. FMN (flavin mononucleotide) acts as a cofactor for the ETC's Complex I enzymatic activity. FAD acts as an electron carrier (FADH2 in its reduced form) that is oxidized at the second complex in the ETC (producing 1 less ATP than NADH due to this position further down the chain).


A number of cytochrome proteins with iron-containing heme groups make up the third and fourth complexes of the ETC, each responsible for shuttling protons across the membrane further building the proton gradient. Lipid soluble cytochrome c assists in moving electrons between the two complexes.

ATP synthase, chemiosmotic coupling

ATP synthase is an enzymatic pump that uses the energy harnesses from protons re-entering the mitochondrial matrix down the proton gradient to perform phosphorylation of ADP + Pi to synthesize ATP. This process is an example of chemiosmotic coupling, using the potential energy of an osmotic gradient to drive chemical reactions.

Proton motive force

The energy stored in the proton gradient and used to drive re-entry of protons to the mitochondrial matrix and coupled ATP synthesis is called the proton-motive force.

Net molecular and energetic results of respiration processes

The ETC is able to convert the energy stored in reduced electron carriers into synthesis of ATP, producing 3 ATP per NADH and 2 ATP per FADH2. In total, respiration produces a net 36 ATP per glucose (38 - 2; cost of 1 ATP per NADH from glycolysis imported into mitochondria).

Pyruvate dehydrogenase complex020
Citric acid cycle262

Regulation of oxidative phosphorylation

Oxidative phosphorylation is most immediately regulated by the presence or absence of oxygen. Without oxygen to act as the final electron acceptor, the proteins of the ETC will remain in their reduced forms, backing up the chain until NADH itself is unable to be reconverted to its oxidized NAD+ form. A backup of NADH in turn will slow the citric acid cycle and force glycolysis to rely on fermentation to recover NAD+.

Mitochondria, apoptosis, oxidative stress

The ETC produces some degree of reactive oxygen species and oxidative stress. One of the proteins of the ETC, cytochrome c, acts as indicative of cellular damage and a signal for apoptosis when found outside of the mitochondria.

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