The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
already in the matrix. This is mainly done by a group of enzymes and carriers collectively
termed the malate/aspartate shuttle. There is also a backup pathway for transfer of electrons
from cytosolic NADH to the mitochondrial ATP synthesis machinery. It is much simpler,
involving no matrix-located components and only two enzymes. Its disadvantage is that it
is less energy-efficient than the malate/aspartate shuttle. Muscles that work extremely hard
for short durations (such as insect flight muscles) use it a great deal. 13 It is called the
s,n-glycerophosphate shuttle.
Also, since ATP (over and above that created by glycolysis) is needed throughout the
cell and not only in mitochondria, it must be transported out of mitochondria after being
made, and conversely its constituent parts, ADP and phosphate, must be imported. These
processes are also done by specialised carrier proteins: ATP and ADP by one, and phosphate
by another. The only other metabolites that need to cross the membrane are oxygen (which
is consumed by the processes described in the rest of this section) and carbon dioxide
(which is generated by those processes); they both cross it quite freely, like water, without
an active carrier.
2.3.3. Mitochondrial Chemistry
2.3.3.1. Creation of Acetaldehyde, as Acetyl CoA: Oxidation
The first degradative process that occurs inside mitochondria is the conversion of
pyruvate and fatty acids to acetaldehyde. These are oxidation reactions, because they involve
the removal of electrons from the major reagents. This process does not make ATP, and
there is no hugely compelling reason why it should not have evolved to happen in the cytosol.
Ostensibly that would have been simpler, because then only one molecule destined for
destruction—acetaldehyde—would need to be imported into mitochondria, as against two
different, larger ones (pyruvate and fatty acids). The likely reason is that, whereas pyruvate
and fatty acids diffuse freely in the cytosol, acetaldehyde is always attached to a carrier
molecule, coenzyme A (CoA), which is quite large (see Fig. 2.4) and is not transported
through the mitochondrial membrane. Both fatty acid oxidation and pyruvate oxidation
end by attaching a molecule of acetaldehyde to CoA, forming acetyl CoA. 14,15 The
attachment involves the liberation of two hydrogen atoms, whose constituent protons and
electrons go to the usual reservoirs.
2.3.3.2. More ATP, but on Borrowed Oxygen: Oxidation (Again)
Acetaldehyde contains two carbon atoms, one oxygen and four hydrogens, and in
mitochondria it is converted into two molecules of carbon dioxide. Clearly this needs a
supply of three atoms of oxygen for each molecule of acetaldehyde. But this is not where the
oxygen we breathe is used: that comes later. Instead, the oxygen is recruited by breaking
down three molecules of water.
The other imbalance between acetaldehyde and carbon dioxide is the hydrogens. The
conversion of one molecule of acetaldehyde and three of water to two of carbon dioxide
releases ten of them. Two of these have already been accounted for by the attachment of
acetaldehyde to CoA; the other eight are released now. All ten go to the reservoirs—ten
protons into the aqueous medium, and ten electrons into five two-electron carriers, which
is this case are four NADH and one FADH2.
The breakdown of acetaldehyde is done by a complex series of reactions (see Fig. 2.5)
that was worked out in the 1930s. The key breakthrough, identification of the cyclic nature
of this series, was achieved in 1937 by Hans Krebs, 16,17 which is why it is often called the
Krebs cycle. Krebs preferred to call it the tricarboxylic acid (TCA) cycle, so I will stick to that
term.