Electron Transport Chain
And when
 It is a series of protein complexes and other
molecules that transfer electrons from electron
donors to electron acceptors via redox reactions
and couples this electron transfer with the transfer
of protons (H+ ions) across a membrane.
 Your heart is constantly working. Whether you’re
swimming or taking a nap, your heart is always on
the go.
 The main form of energy that keeps our heart cells,
and really all of our body cells, going is adenosine
triphosphate, or ATP.
 Mitochondria: the main ATP producing factory.
which has an inner and an outer membrane
 The inner membrane where a process called
oxidative phosphorylation occurs.
“Oxidative” refers to oxidation - which is when a
molecule donates its electron, and “phosphorylation”
which refers to the addition of a phosphate group to
adenosine diphosphate, or ADP, to form ATP.
So Oxidative phosphorylation is the process of
making ATP by Donating electrons to complexes
embedded within the inner mitochondrial membrane.
These complexes are proteins or lipids coupled with
metals like iron and copper that facilitate the
movement of electrons. Together, they form the
electron transport chain.
During the electron transport chain, electrons are
passed on from complex to complex, and finally to
oxygen, creating a proton gradient that will be used to
make ATP.
The electron transport chain begins with two key
molecules that want to donate their electrons:
1. Nicotinamide Adenine Dinucleotide, or NADH
2. Flavin Adenine Dinucleotide, or FADH2
both of which get oxidized in the electron transport
chain.
NADH and FADH2 are primarily generated in the
citric acid cycle which occurs in the mitochondria, but it
can also come directly from glycolysis - which is the
breakdown of glucose in the cytoplasm, or fatty acid
oxidation, which is the breakdown of fats in the
mitochondria. Enzymes called DEHYDROGENASES help
generate the electron-rich NADH and FADH2.
those molecules are coming from the cytoplasm, they
can only enter the mitochondria using a specific shuttle.
When using the malate-aspartate shuttle, electrons
enter the electron transport chain as NADH.
When using the glycerol-3-phosphate shuttle, electrons
enter electron transport chain as FADH2.
There are two entry points into the electron transport
chain.
1. The first point of entry, is where NADH gives its
electrons to Complex I.
Complex I contain flavin mononucleotide - a
derivative of riboflavin or Vitamin B2 - and iron-sulfur
centers called FeS.
NADH gives its electron to flavin mononucleotide,
and it gets turned back to NAD+, and can then be re-
used by dehydrogenases to make more NADH.
2. The second point of entry, is where FADH2 gives
its electron to Complex II.
Complex II which is also called succinate
dehydrogenase - the exact same enzyme that takes part
in the citric acid cycle!
That means that citric acid cycle and electron
transport chain actually share a step, so their activity
Rises and falls together.
3. Ultimately, electrons from complexes I and II
flow directly to Coenzyme Q which is also called
UBIQUINONE.
4. Next coenzyme Q passes on the electrons to a
series of cytochromes, which are proteins that
contain heme groups.
Heme groups contain iron, which is able to grab an
electron and go from Fe3+ to Fe2+.
5. The heme iron can then release the electron to
the next cytochrome in the chain and go back to
Fe3+, so that it’s ready to grab another
electron. It’s a bit like factory chain workers
relaying the electrons between one another!
6. Complex III is made up of cytochrome b and
cytochrome c1, and then electrons move over
to cytochrome c,
 7. and from there the electrons get passed to
complex IV, which is composed of cytochromes
a and a3, which are together referred to as
CYTOCHROME OXIDASE.
Interestingly, the heme groups of complex IV contain
copper rather than iron.
8. Cytochrome oxidase transfers the electrons to
the final electron acceptor, oxygen, making the
oxygen electronegative enough to grab two
protons - making a molecule of H20.
Now, if a cell doesn’t receive enough oxygen, like in
hypoxia, which is the most common cellular injury, then
electron transport chain gets interrupted and ATP
synthesis doesn’t happen.
So, the complexes are responsible for the “oxidative”
part of oxidative phosphorylation – and you can think of
the electron transport chain as a game of hot potato -
with the complexes rapidly passing electrons off to one
another, creating an electrical current.
9. That electrical current creates energy that
drives complexes I, III, and IV to pump positively
charged protons out of the mitochondria and
into the space between the inner and outer
mitochondrial membrane, creating a proton
gradient across the inner mitochondrial
membrane.
That’s because complexes I, III, and IV are the only
ones to span the inner mitochondrial membrane. In
fact, as the electrons are hopping through, the
complexes are changing their conformation to push
protons across.
It’s a bit like how electrons hop wires in a home, and
that energy can be used to do work - like plugging in a
vacuum to suck up dirt. In this case, the little complexes
would be the vacuums, sucking up protons.
Now, this gradient is considered unstable because
the protons are always trying to equilibrate across the
inner mitochondrial membrane, even though it’s totally
impermeable to them.
10. To get across, protons have to use a special
proton channel called F0, that’s attached to an
enzyme called F1.
F1 is an ATP synthase that uses the proton gradient
to phosphorylate an ADP molecule and make ATP –
11. so ATP synthase is in charge of the
“phosphorylation” step of oxidative
phosphorylation. Sometimes it’s called Complex
V of electron transport chain.
Since ATP is formed in the mitochondria, it uses an
ATP/ADP antiport to get pumped out of the
mitochondria and into the cytoplasm, and that way the
mitochondria gets a new ADP molecule, which it uses to
make the next ATP. You can think of it as an ATP
shuttle!
Approximately 1 NADH molecule that donates its
electron to the electron transport chain generates a
proton gradient strong enough to make 3 ATP
molecules, since NADH activates 3 proton pumps -
complexes I, III and IV. whereas, 1 FADH2 molecule only
makes 2 ATP molecules, because FADH2 skips complex
1, and starts at complex 2, activating only 2 proton
pumps - complexes III and IV.
Since both NADH and FADH2 require an oxygen
molecule to ultimately accept their electrons, these
values are called the phosphate to oxygen ratio or p/o
ratio, which is the ratio of ATP produced per oxygen
consumed for each molecule. Again, these are just
approximate ratios.
Electron transport chain isn’t controlled hormonally,
rather it’s controlled by the energy level within the cell
itself.
12. When ATP builds up within a cell, a sign of high
energy, electron transport chain slows down,
and when ADP builds up, a sign of low energy,
electron transport chain speeds up.
Now, it turns out that drugs and chemicals can
effectively “break” oxidative phosphorylation in two
ways - uncoupling and inhibition.
 Uncoupling: Normally, the electron transport chain
is coupled with ATP synthesis, meaning that they
happen together. Uncoupling agents break that link.
They do this by inserting their own proton channels,
called ionophores, into the inner mitochondrial
membrane or by simply carrying the protons back
into the mitochondrial matrix, thereby allowing
them to bypass the F0 subunit of the ATP synthase
enzyme.
 Uncoupling agents dissipate the proton gradient
created by the complexes. And because the protons
enter back into the mitochondria with the
uncoupling agent instead of through the F0
component of ATP synthase, F1 isn’t able to
phosphorylate ADP to make ATP.
Now it’s important to note that the electrons are
still flowing from complex to complex all the way to
the final electron recipient, oxygen.
So red blood cells keep delivering oxygen to the
tissues so that it can be the electron recipient.
Also, as the cell’s ADP levels rise, the body tries
to increase its metabolic rate to make more
electron donors like NADH and FADH2. But this
electron flow is useless, because no matter how
large of a proton gradient there is, the protons just
go back with the uncoupling agent instead of going
through F0.
Because some of the electron’s energy is not used
up in moving protons across the inner
mitochondrial membrane, more of it is available to
turn into heat energy.
There are some endogenous uncoupling agents like:
- Thermogenin, which is a protein found in the brown
adipose tissue of babies, used to generate heat. It is also
found in hibernating animals - so yeah, we’re kind of
like polar bears when we’re babies.
 Uncoupling: is kind of like a car with a hot,
hardworking engine, but despite that, the car isn’t
moving.
Another example of a medication that can be an
uncoupling agent in high doses is aspirin.
The uncoupling can lead to a really high
metabolic rate, which can lead to a metabolic
acidosis, and if ATP levels start to fall too low to
allow the respiratory centers and respiratory
muscles to work, then it can lead to a respiratory
acidosis as well.
A combined metabolic and respiratory acidosis
quickly becomes life-threatening. Okay, the other
way that oxidative phosphorylation can go awry is
by inhibition, meaning that some chemicals and
drugs inhibit components of the electron transport
chain.
Unlike uncoupling, inhibition stops the flow of
electrons through the electron transport chain, and
that leads to a decrease in ATP synthesis. Because
electron flow is put to a stop, electron donors such
as NADH and FADH2 build up, so the body doesn’t
feel the need to make more, and the metabolic rate
falls.
Inhibition is like turning off the car engine, which of
course means that the car won’t move. And not
surprisingly, poisons that work by inhibiting electron
transport chain can lead to death pretty quickly.
Examples of inhibiting:
 Agents include carbon monoxide and cyanide , both
of which inhibit complex IV of the electron
transport chain.
 Barbiturates, which are GABA agonists that can be
effective for seizure disorders, inhibit complex I at
high doses.
 Oligomycin, which is an antibiotic too toxic for
human use, inhibits the F0 component of ATP
synthase.
 Statins, which are a class of lipid-lowering
medications don’t inhibit electron transport chain,
but they can decrease the synthesis of coenzyme Q.
That reduction in coenzyme Q can result in decreased
ATP production and lead to muscle pains and cramps -
and rarely can even cause rhabdomyolysis, which is
when there’s severe muscle breakdown resulting in
kidney failure from the myoglobin released.