Mitochondria electron-transport chain

FIGURE 4.1 Schematics of the mitochondrion. Electron transport chain, proton pumps, and ATP synthase are components of oxidative phosphorylation. Major complexes of electron transport chain are NADH dehydrogenase, bcl complex, and cytochrome c oxidase. The quinone, Q, and cytochrome c are intermediates that shuttle electrons between the complexes. Each of the three complexes is a proton pump. Cytochrome c oxidase is the terminal complex of the electron transport chain. 

Ered Sanger, a double Nobel Prize winner, sequenced the human mitochondrial genome back in 1981. This genome codes for 13 proteins and the mitochondrion possesses the genetic machinery needed to synthesize them. Thus, the mitochondria are a secondary site for protein synthesis in eukaryotic cells. It turns out that the 13 proteins coded for by the mitochondrial genome and synthesized in the mitochondria are critically important parts of the complexes of the electron transport chain, the site of ATP synthesis. The nuclear DNA codes for the remainder of the mitochondrial proteins and these are synthesized on ribosomes, and subsequently transported to the mitochondria. 

What do I mean by a proton concentration gradient Simply, there is a higher concentration of protons in the space between the inner and outer membranes of the mitochondrion than in the mitochondrial interior. The gradient is formed from the energy released in the transfer of electrons down the electron transport chain. Put another way, the released energy is employed to pump protons across the inner mitochondrial membrane into the intermembrane space. 

Oxidizible substrates from glycolysis, fatty acid or protein catabolism enter the mitochondrion in the form of acetyl-CoA, or as other intermediaries of the Krebs cycle, which resides within the mitochondrial matrix. Reducing equivalents in the form of NADH and FADH pass electrons to complex I (NADH-ubiquinone oxidore-ductase) or complex II (succinate dehydrogenase) of the electron transport chain, respectively. Electrons pass from complex I and II to complex III (ubiquinol-cyto-chrome c oxidoreductase) and then to complex IV (cytochrome c oxidase) which accumulates four electrons and then tetravalently reduces O2 to water. Protons are pumped into the inner membrane space at complexes I, II and IV and then diffuse down their concentration gradient through complex V (FoFi-ATPase), where their potential energy is captured in the form of ATP. In this way, ATP formation is coupled to electron transport and the formation of water, a process termed oxidative phosphorylation (OXPHOS). 

Structure of the mitochondrion The components of the electron transport chain are located in the inner membrane. Although the outer membrane contains special pores, making it freely perme-... 

Structure of a mitochondrion showing schematic representation of the electron transport chain and ATP synthesizing structures on the inner membrane. mtDNA = mitochondrial DNA mtRNA = mitochondrial RNA. 

Because of the difficulty of isolating the electron transport chain from the rest of the mitochondrion, it is easiest to measure ratios of components (Table 18-3). Cytochromes a, a3, b, cv and c vary from a 1 1 to a 3 1 ratio while flavins, ubiquinone, and nonheme iron occur in relatively larger amounts. The much larger... 

The chemiosmotic model requires that flow of electrons through the electron-transport chain leads to extrusion of protons from the mitochondrion, thus generating the proton electrochemical-potential gradient. Measurements of the number of H+ ions extruded per O atom reduced by complex IV of the electron-transport chain (the H+/0 ratio) are experimentally important because the ratio can be used to test the validity of mechanistic models of proton translocation (Sec. 14.6). 

The electron transport chain (ETC) or electron transport system (ETS) shown in Figure 16-1 is located on the inner membrane of the mitochondrion and is responsible for the harnessing of free energy released as electrons travel from more reduced (more negative reduction potential, E to more oxidized (more positive carriers to drive the phosphorylation of ADP to ATP. Complex 1 accepts a pair of electrons from NADH ( = -0.32 V)... 

E. Gluconeogenesis requires ATP, which is in short supply, turning up the catabolism of glucose to lactate in the absence of an intact electron transport chain. ADP cannot be transported into the mitochondrion because ATP, its antiporter partner, isn t made by oxidative phosphorylation as a result of cyanide inhibition of cytochrome oxidase. Metabolism of fatty acids and ketone bodies requires a functional electron transport chain for their metabolism, and these possibilities are also ruled out. 

When the levels of ADP and (p) within the mitochondria rise again, oxidation can proceed smoothly and rapidly. It therefore follows that the rate of oxidation of substrate through the electron transport chain is controlled by the concentrations of ADP and inorganic phosphate present in the mitochondrion. When there is plenty of ADP and phosphate, oxidation proceeds smoothly and rapidly. When the concentrations are low, oxidation is correspondingly slow. 

In eukaryotic cells aerobic metabolism occurs within the mitochondrion. Acetyl-CoA, the oxidation product of pyruvate, fatty acids, and certain amino acids (not shown), is oxidized by the reactions of the citric acid cycle within the mitochondrial matrix. The principal products of the cycle are the reduced coenzymes NADH and FADH, and C02. The high-energy electrons of NADH and FADH2 are subsequently donated to the electron transport chain (ETC), a series of electron carriers in the inner membrane. The terminal electron acceptor for the ETC is 02. The energy derived from the electron transport mechanism drives ATP synthesis by creating a proton gradient across the inner membrane. The large folded surface of the inner membrane is studded with ETC complexes, numerous types of transport proteins, and ATP synthase, the enzyme complex responsible for ATP synthesis. 

Mitochondria contain most of the enzymes for the pathways of fuel oxidation and oxidative phosphorylation and thus generate most of the ATP required by mammalian cells. Each mitochondrion is surrounded by two membranes, an outer membrane and an inner membrane, separating the mitochondrial matrix from the cytosol (Fig. 10.18). The inner membrane forms invaginations known as cristae containing the electron transport chain and ATP synthase. Most of the enzymes for the TCA cycle and other pathways for oxidation are located in the mitochondrial matrix, the compartment enclosed by the inner mitochondrial membrane. (The TCA cycle and electron transport chain are described in more detail in Chapters 20 and 21.)... 

The TCA cycle occurs in the mitochondrion, where its flux is tightly coordinated with the rate of the electron transport chain and oxidative phosphorylation through feedback regulation that reflects the demand for ATP. The rate of the TCA cycle is increased when ATP utilization in the cell is increased through the response of several enzymes to ADP levels, the NADH/ NAD ratio, the rate of FAD(2H) oxidation or the Ccf concentration. For example, isocitrate dehydrogenase is allosterically activated by ADP. 

Two major messengers feed information on the rate of ATP utilization back to the TCA cycle (a) the phosphorylation state of ATP, as reflected in ATP and ADP levels, and (b) the reduction state of NAD, as reflected in the ratio of NADH/NAD. Within the cell, even within the mitochondrion, the total adenine nucleotide pool (AMP, ADP, plus ATP) and the total NAD pool (NAD plus NADH) are relatively constant. Thus, an increased rate of ATP utilization results in a small decrease of ATP concentration and an increase of ADP. Likewise, increased NADH oxidation to NAD by the electron transport chain increases the rate of pathways producing NADH. Under normal physiological conditions, the TCA cycle and other... 

Overall, each NADH donates two electrons, equivalent to the reduction of V2 of an O2 molecule. A generally (but not universally) accepted estimate of the stoichiometry of ATP synthesis is that four protons are pumped at complex I, four protons at complex III, and two at complex IV. With four protons translocated for each ATP synthesized, an estimated 2.5 ATPs are formed for each NADH oxidized and 1.5 ATPs for each of the other FAD(2H)-containing flavoproteins that donate electrons to CoQ. (This calculation neglects proton requirements for the transport of phosphate and substrates from the cytosol, as well as the basal proton leak.) Thus, only approximately 30% of the energy available from NADH and FAD(2H) oxidation by O2 is used for ATP synthesis. Some of the remaining energy in the electrochemical potential is used for the transport of anions and Ca into the mitochondrion. The remainder of the energy is released as heat. Consequently, the electron transport chain is also our major source of heat. 

---