The electron transport chain (ETC) is located in the inner mitochondrial membrane. This inner membrane is impermeable to most small ions (including H+, Na+ and K+) and to small molecules such as ATP, ADP, and pyruvate. To move these substances across the inner membrane, the cell uses specific carriers or transport systems.
The mitochondrial matrix contains enzymes for:
The synthesis of glucose, urea, and heme occurs partially in the matrix. The matrix also contains NAD+, FAD, ADP, and Pi, as well as mitochondrial DNA, RNA, and ribosomes.
The ETC is composed of five complexes (I to V). It accounts for the greatest use of oxygen by the body. The ETC is also called the respiratory chain.
Complex I is NADH dehydrogenase. It contains a tightly bound molecule of FMN and includes iron and sulphur atoms.
Complex II is succinate dehydrogenase. It is linked to FAD.
CoQ (Coenzyme Q or ubiquinone) accepts hydrogen atoms from FMNH2 and FADH2 and transfers electrons to Complex III.
Complex III (cyt bc1) and Complex IV (cyt a and a3). Cytochromes contain a heme group (a porphyrin ring plus iron). Electrons move from CoQ to Complex III, then to Cyt c, then to Complex IV. Complex IV (cytochrome oxidase) contains copper atoms and reacts directly with oxygen to form water.
Complex V is ATP synthase (also called F1/F0 ATPase). The F0 domain spans the inner mitochondrial membrane, and the F1 domain appears as a spherical structure that protrudes into the mitochondrial matrix. The chemiosmotic hypothesis states that protons re-enter the matrix by passing through pores in F0. This drives rotation of F0 and causes conformational changes in F1 that allow it to bind ADP and Pi to form ATP.
Proton pump: Electron transport is coupled to phosphorylation of ADP by pumping protons (H+) across the inner membrane from the matrix to the intermembranous space at Complexes I, III, and IV. This creates:
The energy stored in this gradient drives ATP synthesis, coupling oxidation to phosphorylation.
Inhibitors of ETC: These block electron transfer in the ETC at different locations.
i) Amytal and Rotenone (block electron transfer from FMN at Complex I to CoQ)
ii) Antimycin A (blocks Cyt bc1 i.e. C III to cyt c)
iii) Cyanide, CO and Sodium Azide block C IV to O2.
Oligomycin: Binds to F0 on C V and closes the H+ channel, preventing re-entry of protons into the mitochondrial matrix. As a result, electron transport stops.
Uncouplers: These are present in the inner membrane of mammals and humans. They create a proton leak, allowing protons to re-enter the mitochondrial matrix without the energy being captured as ATP. Instead, the energy is released as heat (thermogenesis). UCP 1 is present in brown fat and is seen in neonates. Synthetic uncouplers also increase the permeability of the inner membrane to protons, for example 2,4 DNP, aspirin, and salicylates in high doses, causing fever in toxicity.
Incomplete reduction of oxygen to water produces reactive oxygen species (ROS) such as O2- (superoxide), H2O2, and OH -, which can damage DNA and proteins and cause lipid peroxidation. Cellular defenses against ROS include enzymes such as superoxide dismutase (SOD), glutathione peroxidase, and catalase.
The inner mitochondrial membrane lacks an NADH transporter, so shuttles are used to transfer NADH across the inner membrane. The glycerol phosphate shuttle results in the formation of 2 ATPs for each NADH oxidized, while the malate-aspartate shuttle results in 3 ATPs per NADH oxidized.
Thirteen of the approximately 120 polypeptides involved in oxidative phosphorylation are coded by mitochondrial DNA and synthesized in the mitochondria. Mitochondrial DNA has a 10 times higher mutation rate than nuclear DNA, which can result in mitochondrial myopathies and Leber’s hereditary optic neuropathy. Leber’s hereditary optic neuropathy causes bilateral loss of central vision due to retinal degeneration.
In the intrinsic pathway of apoptosis, pores form in the outer mitochondrial membrane. This causes release of Cyt c from mitochondria into the cytoplasm, which activates proteolytic caspases and leads to cell death.
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