The Electron Transport System, also called the Electron Transport Chain, converts

redox energy available from oxidation of NADH and FADH2, into proton-motive force
which is used to synthesize ATP through conformational changes in the ATP
synthase complex through a process called oxidative phosphorylation.
Oxidation of NADH and FADH2 in the mitochondrial matrix by the electron transport
system links redox energy to ATP synthesis by oxidative phosphorylation
(mitochondrial ATP synthesis) through the establishment of a proton (H+) gradient
across the mitochondrial inner membrane. This "chemiosmotic" process involves the
outward pumping of H+ from the mitochondrial matrix by three protein complexes
in the electron transport system (complexes I, III, IV). The protons flow back down
the gradient through the membranebound ATP synthase complex in response to a
chemical (H+ concentration) and electrical (separation of charge) differential. The
electron transport system consists of the linked redox reactions that occur
sequentially in a set of protein complexes imbedded in the inner mitochondrial
membrane.
What does the electron transport system/oxidative phosphorylation accomplish for
the cell? Generates ATP derived from oxidation of metabolic fuels accounting for
28 out of 32 ATP (88%) obtained from glucose catabolism. Tissue-specific
expression of uncoupling protein-1 (UCP1) in brown adipose tissue of mammals
short-circuits the electron transport system and thereby produces heat for
thermoregulation.
Key enzymes
ATP synthase complex the enzyme responsible for converting proton-motive force
(energy available from the electrochemical proton gradient) into net ATP synthesis
through a series of proton-driven conformational changes. NADH dehydrogenase
also called complex I or NADH-ubiquinone oxidoreductase. This enzyme catalyzes
the first redox reaction in the electron transport system in which NADH oxidation is
coupled to FMN reduction and pumps 4 H+ into the inter-membrane space.
Ubiquinone-cytochrome c oxidoreductase - also called complex III, translocates 4 H+
across the membrane via the Q cycle and has the important role of facilitating
electron transfer from a two electron carrier (QH2), to cytochrome c, a mobile
protein carrier that transfers one electron at a time to complex IV. Cytochrome c
oxidase - also called complex IV pumps 2 H+ into the intermembrane space and
catalyzes the last redox reaction in the electron transport system in which
cytochrome a3 oxidation is coupled to the reduction of molecular oxygen to form
water ( 1 2O2 + 2 e- + 2 H+ --> H2O).
Complex I; NADH-ubiquinone oxidoreductase (NADH dehydrogenase), Complex II;
succinate dehydrogenase, Complex III; Ubiquinone-cytochrome c oxidoreductase,
and Complex IV; cytochrome c oxidase. The fifth enzyme fraction contained the
F1Fo ATP synthase complex (actually purified as an ATP hydrolyzing activity)
consisting of a large multisubunit complex which could be further fractionated into a
membrane bound "stalk" (Fo) and a spherical "head" (F1) encoding the catalytic
subunit.

Metabolic fuel in the form of NADH and FADH2 feed into the electron transport
system from the citrate cycle and fatty acid oxidation pathways. Pairs of electrons
(2 e-) are donated by NADH and FADH2 to complex I and II, respectively, and flow
through the electron transport system until they are used to reduce oxygen to form
water ( 1 2O2 + 2 e- + 2 H+ --> H2O). The two mobile electron carriers in this
series of reactions are coenzyme Q (Q), also called ubiquinone, and cytochrome c
which transfer electrons between various complexes. The stoichiometry of "proton
pumping" is 4 H+ in complex I, 4 H+ in complex III, and 2 H+ in complex IV (10
H+/NADH and 6 H+/FADH2). The donation of 2 e- from NADH in the form of a
hydride ion (:H+) to FMN initiates a series of sequential redox reactions involving as
many as 20 discrete electron carriers, culminating in the reduction of molecular
oxygen to form water. Pairs of electrons as hydrogen atoms (2H+ + 2e-) can also
enter the electron transport system through oxidation of FADH2 molecules
covalentlyattached to enzymes associated with either the cytosolic side of the inner
mitochondrial membrane (mitochondrial glycerol-3-phosphate dehydrogenase), or
that belong to metabolic pathways located within the mitochondrial matrix
(succinate dehydrogenase and ETF-Q oxidoreductase).
Complex I: NADH-ubiquinone oxidoreductase Complex I is the largest of the four
protein complexes in the mitochondrial electron transport system consisting of as
many as 42 polypeptide chains. The function of complex I is to pass 2 e- obtained
from the oxidation of NADH to Q using a coupled reaction mechanism that results in
the net movement of 4 H+ across the membrane. Complex I contains a covalently
bound flavin mononucleotide (FMN) that accepts the two electrons from NADH, as
well as at least six different iron-sulfur centers (Fe-S) that carry one electron at a
time from one end of the complex to the other. The poison rotenone blocks electron
transfer within complex I by preventing a redox reaction between two Fe-S centers.
Complex I passes the two electrons obtained from NADH as a hydride ion (:H-) to Q
(ubiquinone) which has three critical roles in the electron transport system, .1) Q
serves as a mobile electron carrier that transports electrons laterally in the
membrane from complex I to complex III, 2) Q is the entry point into the electron
transport system for electron pairs (2 e-) obtained from the citrate cycle, fatty acid
oxidation and the enzyme glycerol-3P dehydrogenase, and 3) Q has the important
task of converting a 2 e- transport system into a 1 e- transport system which passes
electrons one at time to the mobile carrier protein cytochrome c.
Complex II: Succinate dehydrogenase Succinate dehydrogenase catalyzes an
oxidation reaction that converts succinate to fumarate in a coupled redox reaction
involving FAD. This enzyme was copurified along with other polypeptides that
together constitute complex II of the electron transport system. The 2 e- extracted
from succinate in the citrate cycle is passed through the other protein subunits in
the complex to Q. No protons are translocated across the inner mitochondrial
membrane by complex II. The electron pair donated by succinate to FAD ultimately
leads to the translocation of four fewer H+ than NADH because complex II is not a
proton pump. This is why the ATP currency exchange ratio for FADH2 oxidation is
lower than it is for NADH, giving rise to only ~1.5 ATP/FADH2 instead of ~2.5
ATP/NADH. The same holds true for electron pairs extracted from the FADH2 moiety

of glycerol-3P dehydrogenase and ETF-Q oxidoreductase, both of which donate 2 eto Q.

Complex III: Ubiquinone-cytochrome c oxidoreductase Complex III is the docking site
for QH2 (ubiquinol) and consists of 11 protein subunits in each of two monomer
subunits, the presence of two distinct binding sites for ubiquinone called QP and QN
which play a crucial role in diverting one electron at a time to cytochrome c via the
Q cycle. The terms QP and QN refer to the proximity of the sites to the positive
(inter-membrane space) and negative (matrix) sides of the membrane.
Cytochrome C Cytochrome c (Cyt c) is a small protein of ~13 kDa that associates
with the cytosolic side of the inner mitochondrial membrane and is responsible for
transporting an electron from complex III to complex IV using an iron-containing
heme prosthetic group. Oxidized Cyt c contains ferric iron (Fe3+) in the heme
group and reduced Cyt c contains ferrous iron (Fe2+). The heme group of Cyt c is
covalently attached to the protein through cysteine residues and lies within a pocket
surrounded by three alpha helices.
Complex IV: Cytochrome c oxidase Complex IV accepts electrons one at a time from
Cyt c and donates them to oxygen to form water. In the process, two net H+ are
pumped across the membrane using a conformational-type mechanism similar to
complex I. The mitochondrial complex IV protein consists of two monomers of ~200
kDa that each contain 13 polypeptides, two copper centers (CuA and CuB) and two
heme groups (cytochrome a and cytochrome a3). Cyt c docks on the P side of the
membrane to complex IV near CuA which accepts the electron leading to oxidation
of the heme group in Cyt c (Fe2+ --> Fe3+). The reduced CuA passes the electron
to an iron atom in the heme of cytochrome a which then transfers it to cytochrome
a3. Finally, the e- is passed to CuB which donates it to oxygen.