Eukaryotic ATPase Activity? Hypoxia?

Nigel Wraight AOR at cadvision.com
Thu Sep 6 11:09:01 EST 2001


I have been led to believe that while bacterial ATP synthase can act as
an ion pump, reverse-hydrolysing ATP,  eukaryotic ATP synthase does not
have this "ATPase" activity -- or perhaps, not in vivo?

Can anyone clarify the following result?

J Mol Cell Cardiol 1995 Sep;27(9):1895-1903

Dose/response curves of lipoic acid R-and S-forms in the working rat
heart during reoxygenation: superiority of the R-enantiomer in
enhancement of aortic flow.

Zimmer G, Beikler TK, Schneider M, Ibel J, Tritschler H, Ulrich H.

Micromolar concentrations of lipoic acid racemate added to a working rat
heart during hypoxia have been previously found to improve aortic flow
during subsequent reoxygenation. Since the R-form represents the
naturally occurring form of lipoic acid, and the S-form does not reveal
a positive influence on ATP synthesis in isolated mitoplasts, a
dose/response curve of both
enantiomers has been performed in working rat hearts. After the end of
perfusion mitochondria
were isolated and further analysed. 

At a concentration of 0.05-0.1 mumol of the R-enantiomer, aortic flow
rises precipitously during reoxygenation, reaching over 70% of normoxic
values compared to 50% of the controls. By contrast, with the
S-enantiomer a value of about 60% is attained at 1 mumol, only. 

Accordingly, ATPase activity in mitochondria isolated from rat hearts
previously treated with
0.05-0.1 mumol of the R- or S-enantiomer was significantly decreased or
increased respectively [In the full text, the author explicates: "ATPase
activity (ATP splitting ADP + Pi)" -- ie. not just using "ATPase" as a
synonym for "ATP synthase." Likewise, "ATPase activity increases under
conditions of ischemia/hypoxia. The contrary is found for ATP
synthesis." "There is a prpensity of increase of ATP synthesis within
isolated mitochondria at this concentration of R-lipoic acid which is
connected with a significant fall in ATPase activity."] . Consequently,
whereas mitochondrial ATP synthesis was increased when the R-enantiomer
was previously added to the working heart at 0.05-0.1 mumol
concentration, with the S-enantiomer ATP synthesis remained within the
control range. 

Mitochondrial membrane fluidity, measured with diphenylhexatriene,
revealed a trend towards increase with the R- and decrease with the
S-enantiomer. The total amount of thiol added at 0.1 mumol concentration
is consistent with a value of 2 nmol/mg mitochondrial protein. This
value has previously been found to be connected with -SH groups which
add oligomycin-sensitivity to the ATPase complex. It is suggested that
oligomycin-sensitive mitochondrial -SH groups contribute to the overall
efficiency of low concentrations of lipoic acid R-enantiomer to enhance
aortic flow.

PMID: 8523450 

Indeed, the authors explicitly link a small improvement in aortic flow
at S-enantiomer concentrations of 1 mcmol to a (relative) reduction of
the *increase* in ATPase activity seen at lower concentrations: "It is
significant that for the  S-enantiomer, ATPase activities were increased
[at lower concentrations] whereaas a decrease was noted between 1.5 and
10.0 micmol. This corresponds with the small improvement in aortic flow,
occurring at ... 1 micmol/100mL."

The discussion would seem to provide an explanation, but it's too
"compressed" for my understanding:  "mitochondria ... have long been
recognized as targets of reoxygenation or reperfusion damage ... -SH
groups in the hydrophobic mitochondrial membrane interior first become
unreactive or oxidized [citing Arch Biochem Biophys 266(1):83-8 and
89-97]. Oxidation of -SH groups may contribute to rearrangement of the
F0 subunits of the ATP synthase and may be involved in decreased carrier
functions as well (ie. the ADP-ATP translocator [citing Arzneim Forsch

Isolated F1-particles have ATPase activity; is it possible that
oxidative damage to the ATP synthase complex leads to some dissociation
of the two parts, resulting in F1 ATPase activity? Or is there some
other ATPase that is being monitored? Yet the authors regularly seem to
be speaking of the ATPase activity in terms that seem to associate it
with the oligomycin-sensitive ATP synthase itself.

I would *greatly* appreciate any insight which anyone might be able to
provide in this.



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