The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
But plasma also carries high levels of one very undesirable potential electron acceptor:
oxygen. It has been shown that the PMOR has lower affinity for oxygen than for
nonphysiological electron acceptors such as ferricyanide; 27a,17,28 but not necessarily low
enough to prevent any superoxide production in the plasma surrounding an anaerobic cell.
(A functionally related enzyme, which oxidises NADPH rather than NADH, is found in
leucocytes, and its role is the deliberate production of superoxide outside the cell to act as
a bactericide.) Furthermore, three recent reports 27b-27d show that extracellular superoxide
can indeed be created by cell surface NADH oxidases, in some circumstances.
This superoxide would not be directly problematic. One of our three variants of
superoxide dismutase is specific to the extracellular medium; it will scavenge most superoxide
generated in this way, particularly since it is known to be present at very high levels in the
artery wall. 29 The hydrogen peroxide that is thereby produced will, similarly, be converted
to water by extracellular glutathione peroxidase and/or catalase (see Section 3.5).
Some superoxide, however, will inevitably evade this defense. Superoxide is a relatively
unreactive radical, and cannot autonomously initiate lipid peroxidation; but it has a high
affinity for ferric iron (Fe 3+ ), which it reduces to ferrous (Fe 2+ ). Ferrous iron, in turn,
participates in Fenton reactions: it can react either with hydrogen peroxide, creating the
highly reactive hydroxyl radical, or else with lipid hydroperoxides, creating a lipid alkoxyl
radical. This last reaction is particularly worthy of consideration, because it effects the
“branching” of lipid peroxidation chain reactions, which is the main reason why they
propagate so rapidly 30 (see Section 3.7).
Since iron is an essential component of many enzymes, it must be provided to all cells
after extraction from the diet. This is of course done via the blood stream. But such iron is
maintained in the ferric state, almost certainly protected from reduction by superoxide, by
its carrier protein, transferrin, 31 except possibly during cellular uptake. 32 Another major
iron-carrying plasma protein, ferritin, probably also has a low affinity for superoxide because
of the protective effect of ceruloplasmin, which also binds virtually all plasma copper. 33 A
third major source of iron in plasma is haemoglobin, which is released into plasma by rupture
of red blood cells, especially at sites of inflammation; but it is both removed by haptoglobin
and (according to a recent report) 34 detoxified by haemopexin whenever it assumes the
more unstable ferric state, methaemoglobin. A fourth source, however, appears to have less
such protection. It is haemin.
Haemin is the non-protein component of haemoglobin, composed of an iron atom in
a porphyrin ring. Haemin becomes detached from methaemoglobin at a significant rate
and is prone to desorb from its host red blood cell, becoming free in plasma. Once free, it is
probably not a significant pro-oxidant, because it is assiduously bound by albumin and
haemopexin, the latter of which transports it to the liver for destruction. 35 Recent work, 36
however, has firmly established that haemin which is still suspended in the red cell membrane
also binds—albeit transiently—to low-density lipoprotein (LDL) particles. Crucially, these
studies took care to assess the binding affinities in physiologically realistic conditions. The
authors concluded that haemin may be heavily involved in LDL oxidation in vivo. This is
the reason why the Fenton reaction of ferrous iron with lipid hydroperoxides is so likely to
be important: most of the lipid hydroperoxides present in plasma are in LDL. 37
Adding all this together, it begins to look as though a pathway really does exist whereby
anaerobic cells can be highly toxic to aerobic ones (Fig. 9.3). LDL uptake is not something
that cells can forgo; it is their source of cholesterol, without which their membranes would
lose fluidity and break down, with rapidly fatal consequences to the cell. So if the LDL
available in the blood is becoming increasingly contaminated with pro-oxidants such as
lipid hydroperoxides, the cell has no choice but to import those impurities, whatever the
consequences.