The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
Fig. 3.1. The major destructive reactions relevant to MiFRA, showing their LEC parity.
By this means, arbitrary amounts of oxygen can become incorporated into a material
composed of lipids—such as a membrane—starting from just one lipid radical. This is
deleterious for two reasons. Firstly, the resulting lipid hydroperoxides (LOOH) are less
hydrophobic than the original lipids, so that the membrane will be more permeable to protons
and other ions and thus less able to sustain OXPHOS. 3,4 Secondly, lipid hydroperoxides are
somewhat unstable, and are prone to undergo many kinds of molecular rearrangement,
forming cyclic endoperoxides and other baroque species 5 (see Section 3.8).
But a much worse situation comes about when the medium contains a source of superoxide
and also a trace of a transition metal such as iron. The lipid hydroperoxides formed
above have ceased to be LECs: they are unwelcome in the membrane, but only mildly so as
compared to LECs themselves. But the superoxide is a LEC, and with the help of the metal
atom it can pass its toxic parcel to form a brand new lipid radical, not to mention an aldehyde
which (like a hydroperoxide) is prone to subsequent rearrangements.
O2• — + Fe 3+
O2 + Fe 2+ •
LaOOH + Fe 2+ • + H +
LaO• + H2O + Fe 3+ a Fenton reaction
LaO• Lb• + LcO
This is known as “branching” of lipid peroxidation chain reactions, because if we put
these three reactions in sequence after the two above we start with one lipid radical and end
with two:
La• + O2
LaOO•
LaOO• + LbH LaOOH + Lb•
O2• — + Fe 3+
O2 + Fe 2+ •
LaOOH + Fe2+ • + H + LaO• + H2O + Fe3+ a Fenton reaction
LaO• Ld• + LcO
La• + O2• — + LbH + H + Ld• + La• + LcO + H2O