Electron Transport Chain

The goal of the electron transport chain (ETC) is to create a proton gradient, the proton-motive force of which is used to generate ATP from ADP in oxidative phosphorylation. Aerohic respiration is the most efficient way of generating enery in living systems. In eukaryotes, the inner mitochondrial membrane, which is folded to generate cristae and thereby maximize surface area, are critical for the ETC. NADH and FADH₂ are generated earlier in glycolysis and the TCA cycle. Broadly, these high energy electron carriers transfer their electrons to carrier proteins located in the inner mitochondrial membrane. Then these electrons are given to oxygen in the form of hybride (H-) ions and water is formed. Energy released from transporting these electrons facilitates proton transport at three specific locations. Protons are moved from the matrix into the intermembrane space, creating a proton gradient. Below we’ll go through the different complexes and steps of the ETC.

Complex I is the first of four complexes in the ETC. It’s an enzyme and is called NADH-CoQ oxidoreductase and catalyzes the transfer of electrons from NADH to coenzyme Q (CoQ). First, favin monucleotide (FMN) accepts a hydribe ion from NADH, which is oxidized to NAD+. FMN becomes FMNH₂ and is similar in structure FAD. FMN passes the 2 electrons onto Fe-S centers, which serve as electron “carriers.” In each Fe-S cluster, one Fe is susceptible to oxidation/reduction. Neighboring Fe-S clusters pass these electrons on until they are passed to CoQ. Electron movement is coupled to proton pumping. It is important to note that electron transfers occur far more efficiently through bonds than through space due to a quantum-mechanical process known as “electron tunneling.” CoQ is a lipid-soluble benoquinone. It accepts the two electrons one at a time. As shown in the diagram above, this electron flow drives the pumping of 4 protons. 2 protons are also used to form CoQH₂, also called ubiquinol. All 6 of these protons contribute to the creation of the electrochemical gradient. The first complex is one of three sites where proton pumping occurs. Baradaran R et al. (2013) has crystal structures of the entire respiratory complex I. The overall reaction for Complex I is: NADH + H⁺ + CoQ –> NAD+ + CoQH₂. The step-wise reactions are 1. NADH + H⁺ + FMN –> NAD+ + FMNH₂ , 2. FMNH₂ + 2Fe-S(oxidized) –> FMN + 2Fe-S(reduced) + 2H⁺, 3. 2Fe-S(reduced) + CoQ + 2H⁺ –> 2Fe-S(oxidized) + CoQH₂.

Complex II is also called succinate-CoQ oxidoreductase aka succinate dehydrogenase, which we’ve seen before in the TCA cycle, where succinate is oxidized to fumarate. No protons are pumped by Complex II, but 2 protons from the matrix are consumed when CoQH² is formed. Just like complex I, complex II also transfers electrons to CoQ. However, complex II receives electrons from succinate instead of NADH. When succinate is oxidized to fumarate , FAD is reduced to FADH₂, and FAD is covalently bonded to complex II. FADH₂  is reoxidized when it reduces a Fe-S cluster. THe final Fe-S center reduces CoQ. The net reaction for complex II is: succinate + CoQ + 2H⁺ –> fumarate + CoQH². The step-wise reactions are: 1. succinate + FAD –> fumarate + FADH₂, 2. FADH₂ + Fe-S(oxidized) –> FAD + Fe-S(reduced), 3. Fe-S(reduced) + CoQ + 2H⁺ –> Fe-S(oxidized) + CoQH².

In complex III, also known as CoQH²-cytochrome c oxidoreductase, electrons are transferred from CoQH² to cytochrome c while pumping 4 protons. Cytochromes are poteins with heme groups in which iron is reduced to Fe²⁺ and reoxidized to Fe³⁺. Both CoQ and cytochrome c can move freely in the inner mitochondrial membrane, but aren’t actually part of any of the complexes. The net reaction for complex III is: CoQH² + 2 cytochrome c [with Fe³⁺] –> CoQ + 2 cytochrom c [with Fe³⁺] + 2H⁺. The Q cycle is a good way to describe this mechanism. This mechanistically happens in 2 steps, as shown above. This video also has a good explanation: https://www.youtube.com/watch?v=rOv-X7VFbp0

In complex IV, also known as cytochrom c oxidase, electrons from cytochrome c are transferred to oxygen, resulting in the formation of water. 4 protons are pumped by this complex, and 4 protons are consumed in the formation of 2 water molecules. 4 reduced cyctochrome c’s are oxidized. Their electrons go through a series of redox reactions and eventually reduce oxygen, which forms water. The overall reaction is: 4 cytochrome c [with Fe²⁺] + 4H⁺ + O₂ –> 4 cytochrome c [with Fe³⁺] + 2H₂O.

Overall, the result of the ETC is increased [H⁺] in the intermembrane space of the mitochondria in eukaryotes. This results in a pH drop in the intermembrane space and a volate difference between the intermembrane space and the matrix. Thus, the electro-chemical gradient is created. Different ETC’s are also used in photosynthesis. NADH is responsible for pumping 10 protons (4 in complex I, 4 in complex III, and 2 in complex IV). FAD is responsible for pumping 6 protons (4 in complex III, and 2 in complex IV). As we will see later in the oxidative phosphorylation section, 4 protons are needed to phorsphorylate ADP to ATP. Thus, one NADH molecule can make 2.5 ATP and one FADH2 molecule can make 1.5 ATP.