The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
42 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
An Introduction to Free Radicals Fig. 3.2. Formation and rearrangement of endoperoxides and cyclic radicals. Obviously the more branching there is, the more peroxidation there can be in total (given a supply of superoxide), so this is a particularly dangerous sequence. The main physiological role of Vitamin E (tocopherol) is thought to be its ability to terminate a chain reaction by reaction 22 in Table 3.3, following which it is restored by vitamin C (ascorbate) to a state where it can do it again (reaction 24). 43
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An Introduction to <strong>Free</strong> <strong>Radical</strong>s<br />
Fig. 3.2. Formation and rearrangement <strong>of</strong> endoperoxides and cyclic radicals.<br />
Obviously the more branching there is, the more peroxidation there can be in total<br />
(given a supply <strong>of</strong> superoxide), so this is a particularly dangerous sequence. <strong>The</strong> main<br />
physiological role <strong>of</strong> Vitamin E (tocopherol) is thought to be its ability to terminate a chain<br />
reaction by reaction 22 in Table 3.3, following which it is restored by vitamin C (ascorbate)<br />
to a state where it can do it again (reaction 24).<br />
43
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