The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

A Challenge from Textbook Bioenergetics and Free Radical Chemistry
Fig. 11.1. The Q cycle, with and without a functioning cytochrome b.
peroxidation is mainly initiated by some non-derivative of superoxide, whose production
does fall as a result of loss of OXPHOS, or else because the main initiator is a superoxide
derivative but the rate of that derivation falls. I shall argue along the latter lines.
It has been almost universally assumed for many years that mitochondrial lipid
peroxidation is mainly initiated by hydroxyl radical, HO•. Superoxide is converted (usually
by superoxide dismutase) into hydrogen peroxide, H2O2, which can accept an electron from
Fe 2+ • (or Cu + •), and in so doing splits in two to form HO• and water. HO• is vastly more
reactive than superoxide and will initiate lipid peroxidation at its first opportunity.
In 1996, however, a very thorough computer analysis was done of the various pathways
that can initiate lipid peroxidation in the mitochondrial inner membrane, and it was shown,
based on published rate constants, that a completely different pathway is predicted to proceed
at a much greater rate than the one just described. 12 Superoxide can, instead, acquire a
proton from the aqueous medium—protonation—forming perhydroxyl radical, HO2•, which
is not quite as reactive as HO• but is reactive enough to initiate peroxidation (see Section 3.5).
This path had also been known for a long time, 11,13 but it was generally presumed not to be a
major source of peroxidation in vivo. The reason its involvement was discounted was that the
creation of HO2• is rapidly reversible—the proton comes off again (deprotonation)—and that
that reverse reaction goes much more easily than the original protonation, so that in cells
there is predicted to be essentially no HO2•. 11 There is one caveat, however. The rates of the
protonation and deprotonation reactions vary with the pH of the medium, such that if the
pH is less than about 4.7 the balance shifts, giving less superoxide than HO2•. 13 Now, the pH
inside cells is much more alkaline than that—between 7 and 7.5, in fact—so theoreticians
felt confident in rejecting a role for perhydroxyl. What was overlooked, however, was that
the place where the peroxidation of interest occurs, and so in which the pH is relevant, is the
surface of the mitochondrial membrane. Recall from Section 4.1 that phospholipids, which
are the main constituents of membranes, have a region called the “head group” exposed to
141