O

H3CO

H3CO

H3CO

H3CO

4 H+ Matrix

Intermembrane space

Intermembrane space

NADH NAD++H

NADH-CoQ reductase (complex I)

CoQH2-cytochrome c reductase (complex III)

Cytochrome c oxidase (complex IV)

4 H+ Matrix

NADH NAD++H

NADH-CoQ reductase (complex I)

Fe-S

Fe-S

f Fe-S FAD

Succinate Fumarate + 2 H+

Succinate-CoQ reductase (complex II)

CoQH2-cytochrome c reductase (complex III)

Cytochrome c oxidase (complex IV)

Fe-S

Fe-S

f Fe-S FAD

Succinate Fumarate + 2 H+

Succinate-CoQ reductase (complex II)

▲ FIGURE 8-17 Overview of multiprotein complexes, bound prosthetic groups, and associated mobile carriers in the respiratory chain. Blue arrows Indicate electron flow; red arrows Indicate proton translocation. (Left) Pathway from NADH. A total of 10 protons are translocated per pair of electrons that flow from NADH to O2. The protons released into the matrix space during oxidation of NADH by NADH-CoQ reductase are consumed in the formation of water from O2 by cytochrome c oxidase, resulting in no net proton translocation from these reactions. (Right) Pathway from succinate. During oxidation of succinate to fumarate and reduction of CoQ by the succinate-CoQ reductase complex, no protons are translocated across the membrane. The remainder of electron transport from CoQH2 proceeds by the same pathway as in the left diagram. Thus for every pair of electrons transported from succinate to O2, six protons are translocated from the matrix into the intermembrane space. Coenzyme Q and cytochrome c function as mobile carriers in electron transport from both NADH and succinate. See the text for details.

As shown in Figure 8-17, CoQ accepts electrons released from the NADH-CoQ reductase complex (I) and the succinate-CoQ reductase complex (II) and donates them to the CoQH2-cytochrome c reductase complex (III). Importantly, reduction and oxidation of CoQ are coupled to pumping of protons. Whenever CoQ accepts electrons, it does so at a binding site on the cytosolic (matrix) face of the protein complex, always picking up protons from the medium facing the cytosolic face. Whenever CoQH2 releases its electrons, it does so at a binding site on the exoplasmic face of the protein complex, releasing protons into the exoplasmic medium (intermembrane space). Thus transport of each pair of electrons by CoQ is obligatorily coupled to movement of two protons from the cytosolic to the exoplasmic medium.

NADH-CoQ Reductase (Complex I) Electrons are carried from NADH to CoQ by the NADH-CoQ reductase complex. NAD+ is exclusively a two-electron carrier: it accepts or releases a pair of electrons at a time. In the NADH-CoQ reductase complex, electrons first flow from NADH to FMN (flavin mononucleotide), a cofactor related to FAD, then to an iron-sulfur cluster, and finally to CoQ (see Figure 8-17). FMN, like FAD, can accept two electrons, but does so one electron at a time.

The overall reaction catalyzed by this complex is

(Reduced) (Oxidized) (Oxidized) (Reduced)

Each transported electron undergoes a drop in potential of «360 mV, equivalent to a AG°' of —16.6 kcal/mol for the two electrons transported (see Figure 8-13). Much of this released energy is used to transport four protons across the inner membrane per molecule of NADH oxidized by the NADH-CoQ reductase complex.

Succinate-CoQ Reductase (Complex II) Succinate dehydro-genase, the enzyme that oxidizes a molecule of succinate to fumarate in the citric acid cycle, is an integral component of the succinate-CoQ reductase complex. The two electrons released in conversion of succinate to fumarate are transferred first to FAD, then to an iron-sulfur cluster, and finally to CoQ (see Figure 8-17). The overall reaction catalyzed by this complex is

Succinate + CoQ - fumarate + CoQH2

(Reduced) (Oxidized) (Oxidized) (Reduced)

Although the AG°' for this reaction is negative, the released energy is insufficient for proton pumping. Thus no protons are translocated across the membrane by the succinate-CoQ reductase complex, and no proton-motive force is generated in this part of the respiratory chain.

CoQH 2-Cytochrome c Reductase (Complex III) A CoQH2 generated either by complex I or complex II donates two electrons to the CoQH2-cytochrome c reductase complex, regenerating oxidized CoQ. Concomitantly it releases two protons picked up on the cytosolic face into the intermembrane space, generating part of the proton-motive force. Within complex III, the released electrons first are transferred to an iron-sulfur cluster within complex III and then to two b-type cytochromes (bL and bH) or cytochrome Cj. Finally, the two electrons are transferred to two molecules of the oxidized form of cytochrome c, a water-soluble peripheral protein that diffuses in the intermembrane space (see Figure 8-17). For each pair of electrons transferred, the overall reaction catalyzed by the CoQH2-cytochrome c reductase complex is

(Reduced) (Oxidized) (Oxidized) (Reduced)

The AG°' for this reaction is sufficiently negative that two additional protons are translocated from the mitochondrial matrix across the inner membrane for each pair of electrons transferred; this involves the proton-motive Q cycle discussed later.

Cytochrome c Oxidase (Complex IV) Cytochrome c, after being reduced by the CoQH2-cytochrome c reductase complex, transports electrons, one at a time, to the cytochrome c oxidase complex (Figure 8-18). Within this complex, electrons are transferred, again one at a time, first to a pair of copper ions called Cua2 + , then to cytochrome a, next to a

Heme a

Intermembrane space

Matrix

Matrix

Cytochrome c oxidase (complex IV)

Heme a

Cub2+ Heme a3

Cytochrome c oxidase (complex IV)

▲ FIGURE 8-18 Molecular structure of the core of the cytochrome c oxidase complex in the inner mitochondrial membrane. Mitochondrial cytochrome c oxidases contain 13 different subunits, but the catalytic core of the enzyme consists of only three subunits: I (green), II (blue), and III (yellow). The function of the remaining subunits (white) is not known. Bacterial cytochrome c oxidases contain only the three catalytic subunits. Hemes a and a3 are shown as purple and orange space-filling models, respectively; the three copper atoms are dark blue spheres. [Adapted from T. Tsukihara et al., 1996, Science 272:1136.]

complex of another copper ion (Cub2+) and cytochrome a3, and finally to O2, the ultimate electron acceptor, yielding H2O. For each pair of electrons transferred, the overall reaction catalyzed by the cytochrome c oxidase complex is

(Reduced) (Oxidized)

During transport of each pair of electrons through the cy-tochrome c oxidase complex, two protons are translocated across the membrane.

CoQ and Cytochrome c as Mobile Electron Shuttles The four electron-transport complexes just described are laterally mobile in the inner mitochondrial membrane; moreover, they are present in unequal amounts and do not form stable contacts with one another. These properties preclude the direct transfer of electrons from one complex to the next. Instead, electrons are transported from one complex to another by diffusion of CoQ in the membrane and by cytochrome c in the intermembrane space, as depicted in Figure 8-17.

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