damaged mitochondria

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Wed Dec 1 07:19:48 EST 1999

Paul Brookes wrote:

> Aubrey commented......  "In my view, damage to the mitochondrial DNA is 
> likely to matter most, because it is hardest to repair."
> I beg to differ, on the basis that mechanisms for the degradation of 
> oxidatively damaged proteins are also virtually non-existant except for
> the proteasome.  It is also unknown how modifications such as tyrosine 
> nitration (by ONOO- ?) might be removed/recycled.   

No, there is one other well-known mechanism (which is the basis for my
original statement): lysosomal autophagocytosis.  It has been known for
30 years or so that mitochondria are perpetually recycled in all cells,
especially postmitotic cells, by autophagocytosis of some and division
of others.  This process necessarily repairs all non-DNA components of
mitochondria, because mitochondrial division necessarily entails the
incorporation into the mitochondron of new lipid and protein, which is
built from scratch rather than by replication of the existing molecules
so is pristine, and thus the pre-existing oxidative (or other) damage is
diluted out.  This was raised by Alex Comfort in 1974 as a reason why
mitochondria could not underlie aging, because he reasoned that the
mtDNA would also be kept at a constant level of damage by preferential
elimination of mitochondria with damaged DNA.  It took 19 years before
Muller-Hocker showed that the reverse is true (the mutant mtDNA wins).

> One interesting possibility is that oxidative DNA damage might not
> actually be occuring at the nuclear or mitochondrial level - it could
> be at the free nucleotide level, and the rates of turnover/incorporation
> of damaged nucleotides may account for the increased damage seen in
> mitochondrial DNA - anyone got figures on these rates?

Interesting, yes.  I know of no data.

> It's hard to see how the things that damage DNA (mainly hydroxyl
> radical in the case of 8'OHG) can reach the chromosome which is in the
> intermembrane space, when the main site of superoxide generation is
> inside the matrix.

The mtDNA is emphatically not in the intermembrane space, it's in the
matrix.  However.... my (as yet unpopular) view is that intermembrane
space superoxide matters more, because (a) the pH is low there, so a
lot of it becomes perhydroxyl radical, and (b) there is no SOD there.
People have argued that cytochrome c does the job of SOD by stealing
back the odd electron, but there is compelling contrary evidence: SOD
targeted to the intermembrane space improves yeast's tolerance of
oxidative stress (BBRC 256:63-67) and there is nonenzymatic dismutation
as indicated by singlet oxygen (Histochem J 29:229-372).  I therefore
think that the major route of oxidative mtDNA damage may be by lipid
peroxidation chain reactions that begin in the intermembrane space
and propagate through the inner membrane to the mtDNA (which is
attached to the inner membrane).  I think hydroxyl radical is almost
as over-rated as ONOO- :-)

> WRT the original question, while ATP loss is probably a major contributor 
> to the effects of mitochondrial dysfunction on the cell, it should be 
> remembered that mitochondria do a whole lot of other things such as the 
> urea cycle and various anaplerotic reactions.

Absolutely.  It is instructive that we can readily generate cells with
no mtDNA but have so far failed to generate cells with no mitochondria.

> Also note a key criticism of mitochondrial dysfunction experiments done
> in cultured cell lines......  you can expose many different cell lines
> to large concentrations of cyanide and have no effect on ATP/ADP
> ratio.   Because cell lines derived from tumours are adapted to
> hypoxia, they have excellent glycolytic capacity and can maintain ATP
> in the face of mitochondrial dysfunction.   I could go into a rant here
> about the mistakes made in examining mitochondria's role in apoptosis
> in cell lines (briefly, apoptosis requires ATP, so mito' dysfunction
> must be a late event in the cascade), but that's another story.

Well said -- I couldn't agree more.

Aubrey de Grey

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