What are the cofactors for each complex in the Electron Transport Chain (ETC)?

Cofactors for Each Complex in the Electron Transport Chain

The electron transport chain (ETC) complexes rely on specific cofactors to facilitate electron transfer, with Complex I using FMN and iron-sulfur clusters, Complex II using FAD and iron-sulfur clusters, Complex III using heme groups and iron-sulfur clusters, and Complex IV using copper centers and heme groups. 1

Complex I (NADH-Ubiquinone Oxidoreductase)

• Uses NADH as the electron donor, which transfers electrons to flavin mononucleotide (FMN) 1
• Contains multiple iron-sulfur (Fe-S) clusters that serve as electron carriers 1
• The electron transfer pathway in Complex I begins with NADH oxidation and ends with ubiquinone reduction 2

Complex II (Succinate-Ubiquinone Oxidoreductase/Succinate Dehydrogenase)

• Contains a covalently bound flavin adenine dinucleotide (FAD) cofactor that is essential for its function 3
• The FAD is linked via an 8α-N3-histidyl linkage to the protein, which is critical for maintaining proper positioning of the isoalloxazine group 3
• Contains iron-sulfur clusters that transfer electrons from succinate oxidation to ubiquinone 1
• Functions both as part of the tricarboxylic acid (TCA) cycle and the electron transport chain 4
• The covalent FAD linkage is essential for maintaining proton transfer pathways through interactions with histidine and glutamine residues 3

Complex III (Ubiquinol-Cytochrome c Oxidoreductase)

• Contains heme groups (cytochrome b) that participate in electron transfer 1
• Includes an iron-sulfur protein known as the Rieske protein with a [2Fe-2S] cluster 1
• Transfers electrons from ubiquinol to cytochrome c 1
• Site IIIQo in Complex III is a major site of reactive oxygen species (ROS) generation 2

Complex IV (Cytochrome c Oxidase)

• Contains copper centers that serve as electron carriers 1
• Includes heme groups (cytochrome a and a3) that facilitate electron transfer 1
• Functions as the terminal electron acceptor complex, transferring electrons from cytochrome c to molecular oxygen 1
• Oxygen serves as the terminal electron acceptor at Complex IV, generating the proton electrochemical gradient necessary for ATP synthesis 1

Complex V (ATP Synthase)

• While not directly part of the electron transfer process, ATP synthase utilizes the proton gradient generated by Complexes I-IV 1
• Contains the F1 catalytic domain and the Fo proton channel domain 1
• The ε-subunit of bacterial F1Fo ATP synthase can undergo conformational changes upon ATP binding 1

Important Considerations

• The electron transport chain can operate through two main pathways: Complex I/III/IV with NADH as substrate, or Complex II/III/IV with succinate as substrate 2
• Iron and copper are essential nutrients for ETC function, serving as cofactors for enzymes with heme and iron-sulfur centers 5
• Respiratory complexes can assemble into larger structures called supercomplexes (SCs), which can modulate ETC organization according to metabolic state 6
• Excessive ROS generation at specific sites in the ETC (sites IF and IQ in Complex I, site IIF in Complex II, and site IIIQo in Complex III) can lead to oxidative stress and cellular damage 2

Understanding the cofactors involved in each complex is crucial for comprehending mitochondrial function, bioenergetics, and the pathophysiology of mitochondrial disorders.