The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

The Search for How So Few Anaerobic Cells Cause So Much Oxidative Stress
9.5. PMOR: The Solution, or the Problem?
Lawen’s group did not extend this work beyond these in vitro experiments, in which
the impermeable electron acceptor was provided in sufficient quantity that it never ran out.
If such a system is functioning in the body, however, something more must be going on. The
electrons must become attached to some molecule in the plasma. If that molecule were an
antioxidant, that would be fine.... but there are other options. The most dangerous one is
that they could reduce transition metal atoms, such as iron and copper. The reduced (“ferrous”
and “cuprous”, as opposed to “ferric” and “cupric”) forms of these atoms are the ones with
the capacity to cause “branching” of lipid peroxidation chain reactions, which are probably
the most powerful amplifiers of oxidative stress (see Section 3.7).
It should now be evident why the PMOR is relevant to the paradox of such low numbers
of anaerobic cells. It is clear that cells whose mitochondria are healthy nevertheless suffer
considerably increased oxidative stress in old age, disproportionate to the overall energy
shortfall of the tissue. The levels of the various markers of oxidative stress rise with age in
all cells, including rapidly-dividing ones. 24 Thus, either these mitochondrially healthy cells
must have an independent intracellular source of oxidative stress—i.e. the mitochondrial
free radical theory of aging, if stated strongly enough to be a real theory of aging (see
Section 7.1), is wrong—or the toxicity of the mitochondrially mutant cells must somehow
be getting greatly amplified. If the PMOR is “hygienic” in disposing of electrons in vivo,
donating them only to antioxidants and thus generating no toxic extracellular products,
then it becomes difficult to see how anaerobic cells can be blamed for systemic oxidative
stress. But perhaps, just perhaps, this flow of electrons out of anaerobic cells might be the
first step in a toxicity-amplification process, since it might not be hygienic: those electrons
might become lonely and create LECs in the blood, which might initiate chain reactions as
described in Section 3.7. This, then, would resemble the situation at the mitochondrial
inner membrane—“reductive stress,” as it would most appropriately be termed (see
Section 5.6.2).
9.6. Systemic Consequences: The "Reductive Hotspot" Hypothesis
So far so good; but, just like the idea of biased destruction rather than biased replication
as a means of proliferation of mutant mtDNA, this speculation is not of much use unless
and until it can be fleshed out into a reasonably detailed mechanism. I thus sought such a
mechanism: in particular, one which allowed the possibility that peroxidation chain
reactions might result at some stage, since that might plausibly provide the required degree
of amplification, enabling the observed small number of anaerobic cells to generate the
observed high levels of age-related oxidative stress.
An important, and powerfully antioxidant, electron acceptor in blood plasma is
ascorbate (vitamin C). As was summarised in Section 3.5, it mainly acts by donating an
electron to a lipid radical (generally via tocopherol, vitamin E) so as to terminate a lipid
peroxidation chain reaction; in doing so it becomes ascorbate radical. Pairs of ascorbate
radicals rapidly react, undergoing disproportionation, which gives one molecule of ascorbate
and one of dehydroascorbate. The latter has no antioxidant capacity, and must be turned
back into ascorbate by the addition of two electrons. It had been proposed 17 that this last
step is a physiological role of the PMOR; no other physiological extracellular electron acceptor
for the PMOR* has been identified. 25 So at first, it seemed that no avenue existed for electrons
to find their way into toxic LECs.
* The enzymes of the PMOR do appear to interact with membrane-bound species, including ubiquinone and
protein disulphides. 26 But, because these are membrane-bound, it is necessary to regard them as components
of the PMOR, rather than substrates.
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