The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

The Search for How So Few Anaerobic Cells Cause So Much Oxidative Stress
them. 48 This glutathione peroxidase can probably also act on phospholipids at the surface
of LDL particles, 48 but, crucially, most of the oxidisable material in LDL is deep inside the
particle and inaccessible to most antioxidants. (Lipid peroxidation must begin at the surface
of the particle, but it will then rapidly undergo chain reactions and other molecular
rearrangements that spread the damage into the cholesteryl ester core.) The protein
component of LDL is also prone to undergo oxidation 49 —indeed, there is evidence that
oxidation of that protein is the feature that the standard LDL receptor uses in order to avoid
importing heavily oxidised LDL (see Section 4.3)—and protein hydroperoxides thus formed
can stimulate further LEC production after import into cells, just like lipid hydroperoxides. 50
For these reasons, it seems quite probable that the particular pathway described earlier,
via the PMOR, oxygen, haemin and LDL, is the primary route transferring oxidative stress
from anaerobic cells to aerobic ones. Extensive evidence supporting this mechanism has
since emerged. 51
9.7.1. Mechanical or Electrical Pathways
The fact that muscle fibers become anaerobic in short segments allows a radically
different mechanism for the propagation of oxidative stress to mitochondrially healthy
regions. I do not think, on current evidence, that it is likely to be correct; however, the
history of science is so littered with failures of such intuition that it would be remiss not to
mention it. This caution is particularly germane in the context of mitochondria, since it was
just such a failure of intuition that induced bioenergeticists to cling for so long to the belief
in a chemical intermediate in OXPHOS (see Section 2.3.4).
The function of a muscle fiber depends critically on two features which are properties
of the fiber as a whole, rather than of each section of it independently. They are that it must
be able to transmit both electrical potential and tensile force along its length. The electrical
potential (the action potential) is necessary because it is the stimulus, starting from the
motor neuron attached to the fiber, that induces each contractile unit of the fiber (termed a
sarcomere) to contract. The tensile force is necessary because, ultimately, a muscle can only
work if it pulls together the two things that are attached to its ends, and (like any chain) it is
only as strong as its weakest link.
Now: it is likely that an anaerobic segment of a muscle fiber undergoes many changes
of cellular chemistry in order to adapt to the absence of OXPHOS. There will probably be
changes to many fundamental aspects of the cytoplasm and the organelles, such as the
NAD + /NADH ratio, the ubiquinone/ubiquinol ratio, and maybe even the pH. There is no
known way in which such changes could affect the fiber’s conductivity—its ability to transmit
the action potential—but the possibility cannot be absolutely discounted at this point.
Similarly, the fiber’s tensile strength would not obviously be affected in an anaerobic region,
since it derives from highly stable intracellular proteins which should be impervious to such
changes, but again there may be vulnerabilities which we have not yet discovered.
Let us then suppose, for a moment, that a muscle fiber does indeed suffer with regard
to either its electrical or tensile integrity. What might that cause? The fiber is quite tightly
attached to its neighbours, so tensile strength is shared; however, the attachments between
fibers might be over-stressed in this situation and weaken. Consequently it is conceivable
that quite large regions of mitochondrially healthy fibers suffer unusually large tensile forces
as a result of small anaerobic segments nearby. This may have consequences for turnover of
muscle protein; that, in turn, may conceivably contribute to oxidative stress. The gaps in
this theory are clearly extremely large, but that is its only serious shortcoming; hence it
would be premature to dismiss it out of hand at this stage.
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