damaged mitochondria

Paul S. Brookes. brookes at uab.edu
Tue Nov 30 14:19:49 EST 1999


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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.   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?.  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.

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.

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.

Paul


_________________________________________
Dr. Paul S. Brookes.            (brookes at uab.edu)
UAB Department of Pathology,   G004 Volker Hall
1670 University Blvd., Birmingham AL 35294 USA
Tel (001) 205 934 1915     Fax (001) 205 934 1775
http://peir.path.uab.edu/brookes

The quality of e-mails can go down as well as up

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<html><div>Aubrey commented......&nbsp; &quot;In my view, damage to the
mitochondrial DNA is likely to matter most, because it is hardest to
repair.&quot;</div>
<br>
<div>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.&nbsp; It is also unknown how modifications such as
tyrosine nitration (by ONOO- ?) might be removed/recycled.&nbsp;&nbsp;
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&nbsp; figures on these rates?.&nbsp; 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.</div>
<br>
<div>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.</div>
<br>
<div>Also note a key criticism of mitochondrial dysfunction experiments
done in cultured cell lines......&nbsp; you can expose many different
cell lines to large concentrations of cyanide and have no effect on
ATP/ADP ratio.&nbsp;&nbsp; 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.&nbsp;&nbsp; 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.</div>
<br>
<div>Paul</div>
<br>
<br>

<font color="#000080">_________________________________________<br>
</font><font color="#FF0000"><b>Dr. Paul S.
Brookes.</b>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
(brookes at uab.edu)<br>
</font><font color="#000080">UAB Department of Pathology,&nbsp;&nbsp;
G004 Volker Hall<br>
1670 University Blvd., Birmingham AL 35294 USA<br>
Tel (001) 205 934 1915&nbsp;&nbsp;&nbsp;&nbsp; Fax (001) 205 934
1775<br>
<a href="http://peir.path.uab.edu/brookes" eudora="autourl">http://peir.path.uab.edu/brookes</a><br>
<br>
<b>The quality of e-mails can go down as well as up<br>
</font></b></html>

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