cron-web.org

[A1CR]

[posted on behalf of MR]

On 9 Nov 2000

GW wrote:

>Hi MR,
>
>Would you please do a short review on:
>
>1) What type of free radicals are generated by the mitochondria.

Superoxide.

>2) What is the normal chain of anti-oxidant reactions which normally quench
>them.

Effectively and directly on site: it depends WHERE. On the "very" inside
(the matrix), MnSOD (manganese superoxide dismutase -- also mtSOD);
however, this produces H202. H2O2 can be detoxed by GSH-peroxidase or
catalase, but appears not to be, effectively -- levels probably
unavoidably too low, the chain rarely complete, and the intermediates
unsafe. Viz tocopherol-mediated peroxidation, etc.

H2O2, if unquenched, can become hydroxyl radicals via interactions with
transition metals -- worse than when you started. Contrary to what we're
always being told, there are NO (that's *NO*) effective hydroxyl radical
scavengers in vivo: the thing is just too virulent for a meaningful physiological
concentration of any given substance to effectively inhibit it from
attacking the first thing it can dig its nasty little razors into.
Fortunately, this may not happen all that often in real conditions;
unfortunately, there's little better happening.

Perhydroxyl is also formed by superoxide joining with H+; don't know
about how this is dealt with, off-hand, &am not fully convinced of its
relevance. Aubrey's book discusses this possibility; I find the relevant
chapter (11) very difficult to follow.

Outside the mt, the standard chain is as above, but starting with
CuZnSOD (or "cytosolic" ctSOD, for obvious reasons). Same chain, but
much more effective (probably) because of free access to later steps in
the chain by GSH-Px &catalase, &the presence of other AOs.

However, the damage which they prevent may not be of much relevance to
aging in higher organisms: levels of such endogenous AOs tend to be
INVERSELY correlated with species max LS, presumably because they are
not getting at the fundamental root of aging-related damage &thus are
discarded as a waste of resources when the REAL cause is effectively
dealt with. NB that GSH goes DOWN in most tissues on CR. And while mice which
are knockouts for MnSOD simply die in utero, those for ctSOD appear to
live largely normal lives (at least until midlife -- nothing further
known AFAIK) unless exposed to conditions where NON-MT free radicals are
at high leves (eg. hyperoxia).

Aubrey's MiFRA provides a good explanation as to why this might be so --
an explanation which also works with other MiFRAs, like Hagen/Ames', or
Brunk's. Please don't ask for a summary: read the book!

In the mt intermembrane space: no effective on-site antioxidants. Hence
(arguably) the inverse relationship mentioned above with the endogenous
AOs ans max LS.

>3) What, if any, anti-oxidant supplements are effective in dealing with those
>not naturally quenched.
>
> A) Inside the mitochondria.

None, direly, effectively, and on-site.

> B) Those which manage to "Leak" out.

Depends: both many and few. Superoxide itself is only really effectively
dealt with by a very small number of supplemental AOs; carnosine is the
only one that comes up offhand, tho' I'm sure there are others (being
very lazy here -- sorry!). H2O2 may be similar: I'm sure there are good
dietary AOs, but can't think of any. More hopeful are some indirect
boosters of the endogenous chain, like vitamin E for SOD and NAC and Se
for GSH-Px. And as noted recently, GSH, if elevated, can accelerate ROS
damage to mt. So what do you do about that.

Further downstream, it's really a "take your pick" scenario: C, E,
flavonoids -- depending on the environment, could be any number of
things. People who say, blank out, "X is a potent antioxidant" are full
of it: different AOs are effective to different degrees in different
media against different ROS. Network AOs, and lipoic acid esp, are
probably the most important defense. But the damage has been done: vis
the failure of
dietary AOs to affect max LS.

The only real solution is to cut production (and we know the only known
way to do that, don't we?), or to reduce the mt's intrinsic
vulnerability -- for which animal evidence shows (to my mind
conclusively) may be accomplished by minimizing long-chain PUFA, and
PUFA in general.
>
>You don't need to ref papers here, just a "Off the Cuff" review as you
see it.

The above was pretty damned off-the-cuff . I hope it's of some help.

-MR