The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

148
The Mitochondrial Free Radical Theory of Aging
addition of FCCP will cause a slower response, dependent on the rather few protons that
leak out of the localized coupling system. In fact, the kinetics in the two cases are the same. 40
11.3.5. Proton Conduction Very Close to a Phospholipid Membrane
So much for the idea of one-dimensional proton movement; what about two
dimensions? The definition of the two-dimensional model is that protons involved in
OXPHOS can move freely within the vicinity of the mitochondrial membrane, but
(for some reason) cannot move away from the membrane. The challenge, therefore, was to
identify such a reason.
First of all we must be clear about the relationship between Mitchell’s model and the
surface effects described in Section 11.2.2. Mitchell asserted that the water throughout the
cytosol, including right up to the membrane, was always electrochemically homogeneous
(due to the very fast conduction of protons): the combination of pH and electrical potential
was uniform. This is not to say that the pH is uniform right up to the membrane—there is
no doubt that the pH is lower near the membrane, as explained in Section 11.2.2—but
rather that the gradient in pH (see Fig. 11.2) is exactly cancelled out by a gradient in electrical
potential (Fig. 11.3). In particular, Mitchell’s model did not allow for any non-uniformity
deriving from proton pumping.
The theoretical breakthrough (or so it briefly seemed) that Tedeschi had failed to provide
came in 1979, when Douglas Kell proposed a reason why the pH right at the membrane may
indeed be influenced by proton pumping, without a counteracting change in electrical
potential there. 41 This can only be so if there is some barrier to the movement of protons in
the direction perpendicular to the mitochondrial membrane, so that they cannot move
equally freely in all three dimensions. He named his model the “electrodic” view, for reasons
which will become apparent.
The idea relies on the details of how water conducts protons, which is very different
from how metals do it. We saw in Section 11.3.1 that this conduction is fantastically rapid;
the way this works at the molecular level is called the Grotthuss* mechanism, 42,29 which
makes use of two properties of water:
1. That each hydrogen atom is linked by a covalent bond to one oxygen atom and by a
hydrogen bond to another, and
2. That excess protons are always bound to water molecules, making hydronium, H3O + .
Conduction is a two-step “hop and turn” process, whereby in step one hydrogen bonds
become covalent and covalent bonds become hydrogen bonds, and in step two some of the
water molecules rotate to allow another hop (Fig. 11.4). The rotation part is proposed 43-45
as an explanation of why ice conducts much better than water, despite being composed of
molecules whose freedom to rotate is clearly less than in liquid water: in ice the tendency of
water molecules to dissociate is much less, so that “neutral pH” is about 10.5, and this
reduction in the number of protons present at any one time means that protons can usually
hop by quantum tunneling, for which the rotation step is not necessary.
There is one more feature of the pH near a phospholipid membrane that we must
bring into play before Kell’s idea can be presented. The acidity of the membrane head groups
must create not only an acidic environment but a steeply graded one—that is, an electric
field, similar to that surrounding an electrode immersed in water. Now, some molecules
* The paper in which de Grotthuss suggested this mechanism 42 is the oldest publication referenced in this
book, dating from 1806. It is amusing to note that he suggested it as a general mechanism for the transmission
of charge in ionic solutions, a hypothesis which was rapidly shown to be false; thus, by the attachment of his
name to the mechanism of proton conduction he has been honored for an idea which was almost, but not
quite, completely wrong.