The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
Finally, some free radicals have decidedly un-free-radical-like chemistry. (That is to
say, to the chemist they are perfectly free-radical-like, but they diverge sharply from the
popular impression.) Nitric oxide (NO), for example, is a free radical, but its only likely
toxicity arises from possible reactions with other free radicals; 1b in my view it probably
plays an insignificant role in free radical toxicity, whereas it certainly has many vital beneficial
functions. This is the last you will hear of NO in this book.
There is a term commonly in use in the literature which may appear to remedy this
terminological deficiency, but in fact it is very little better. The term reactive oxygen species,
or ROS, is used to cover free radicals that behave as radicals are popularly imagined to, but
not ones that are beneficial. But the utility of this term is completely spoilt by its being
defined also to include certain non-radicals, particularly hydrogen peroxide, which are highly
prone to react with radicals and reduced metal ions. This, together with the non-inclusion
of atoms or molecules which behave similarly but are not oxygen-centred, destroys any
chance that there might have been to use “ROS” to describe the relevant chemistry in an
orderly manner that might be easy to master.
In view of this dismal state of affairs I have decided to coin a new term, defined as
covering those molecules or atoms which behave, in biological systems, in a manner that
accords with the popular impression of what a free radical does. Such atoms or molecules
all possess a “lonely” electron—one which either (a) is prone to detach from its host atom or
molecule and move to another (is reductively reactive), or (b) is prone to pull another electron
(which may not itself have been lonely) away from some other atom or molecule (is
oxidatively reactive). This includes many molecules that would be called free radicals by the
strict definition, but not diradicals like molecular oxygen; it also includes transition metal
ions that are in a reductively reactive state where one electron is prone to escape. So these
atoms or molecules will hereafter be termed "lonely electron carriers" or LECs.
The explanatory value of this term will, I hope, become clear in the next three sections.
Meanwhile, Table 3.1 summarises the terminological alternatives.
3.2. What Do LECs Do?
LECs react—with each other and also with non-LECs. You may have wondered what
was so special about having a lonely electron that merited being given a name; this is the
answer. It is vital for life that cells keep tight control over what reactions do and do not
occur, because if unwanted reactions occur then the chemicals that we are made
of—proteins, lipids, nucleic acids—are damaged or destroyed. LECs, if and when they
arise in cells or in the extracellular medium, are particularly prone to initiate unwanted
reactions, and cells employ fantastically sophisticated means to keep them under control.
This control is not always negative—in certain environments, LECs are produced on
purpose and are useful—but MiFRA concerns the more typical situations in which they
are toxic to us.
3.3. Where Do LECs Come From In Vivo?
A class of reaction that LECs are very prone to undergo, and which will be discussed
extensively in this book, starts with one LEC and one non-LEC and transfers one electron
between them, so that the LEC becomes a non-LEC but the non-LEC becomes a LEC. (The
electron may move from the LEC to the non-LEC, or from the non-LEC to the LEC: this is
determined mainly by which LEC is involved, and to a lesser extent by which non-LEC.)
This is therefore a chain reaction, “passing the parcel.” But of course one can’t get this chain
reaction until one has a LEC in the first place.
Unfortunately there is a way that LECs can, and often do, arise de novo inside cells. In
principle, one could create two LECs from none, by taking a molecule all of whose electrons