The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

An Introduction to Mitochondria
and FAD. The resulting NADH goes straight to Complex I, but the FADH2, just like that in
Complex II, is trapped within the relevant enzyme, fatty acyl CoA dehydrogenase. Again
like Complex II, this enzyme resides in the inner membrane and also catalyses the transfer
of the electrons from FADH2 to coenzyme Q and on to Complex III.
The depiction of the respiratory chain in Figure 2.7 implicitly includes the fatty acyl
CoA and s,n-glycerophosphate dehydrogenases and the malate/aspartate shuttle as members.
This is not in fact customary: more usual is to define the respiratory chain as composed
only of Complexes I to IV. I think this is illogically TCA-ocentric, however, and prefer the
expanded definition implied in Figure 2.7.
2.3.4. Mitochondrial Physics: Oxidative Phosphorylation
The alert reader may have noted the conspicuous absence of ATP from Section 2.3.3.3.
It will resurface here, along with an explanation of why the conversion of oxygen to water
involves such suspiciously intricate machinery.
2.3.4.1. The Curious Isolation of Complex V
Everything discussed is Section 2.3.3 was known by 1953. It was also known that cells
made hugely more ATP than could be accounted for by the contributions of glycolysis and
the TCA cycle; moreover, the enzyme which made the “missing” ATP was characterised not
long afterwards. 20 Like the components of the respiratory chain, it is a highly sophisticated
structure in the mitochondrial inner membrane; naturally it is termed Complex V (or,
alternatively, ATP synthase or ATPase).
There was a problem, however. It was quite clear that the respiratory chain had to be,
somehow, driving ATP synthesis by Complex V. It was releasing the required amount of
energy—it had to be, because it was mediating the reaction of hydrogen with oxygen to
make water. This clear linkage gave rise to the term oxidative phosphorylation, or OXPHOS,
to describe mitochondrial function—the linkage of oxidative processes (described above)
with the phosphorylation of (addition of phosphate to) ADP making ATP. The difficulty
was that there was no apparent physical or chemical linkage (coupling, as it is usually
termed) between the respiratory chain and Complex V. Somehow there had to be a transfer
of energy between the two, but exactly how was a mystery that resisted elucidation for
many years more. This transporter of energy was so central to the description of other
biochemical processes that biochemists resorted to a special notation for talking about it:
it was denoted “~”. I think this was a good choice, evoking very clearly the despair felt by
those struggling to identify it.
2.3.4.2. The ATP Goldmine: Chemiosmosis
This last major part of the puzzle of mitochondrial function fell into place, with rather
a fight, starting in 1961 with the publication by Peter Mitchell of the chemiosmotic
hypothesis. 21 Mitchell’s pivotal breakthrough was to identify an assumption that everyone
was making but which was unfounded. The assumption was that, in cells, the only way to
get energy from one molecule to another was in chemical reactions. Granted, that was how
it had always been found to be done; but just because a process was happening in cells, that
did not prohibit the process from using the other types of energy that are familiar in physics.
Mitchell realised that electrochemical potential energy was a perfectly realistic candidate in
this case. The enzymes between which energy was being transferred all reside in the inner
membrane of mitochondria, and that membrane is, by and large, impermeable to ions.
Therefore, it was conceivable that the respiratory chain was generating a disparity in the
concentrations of one or another ion on either side of this membrane. Basic thermodynamics
tells us that that disparity takes energy to create, and that energy is released as and when it is
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