Purine release: a protectivesignaling mechanismof the mitochondrial permeabilitytransition pore in ischemia
Sergiy M. Nadtochiy, Dhananjaya Nauduri1,Tatyana V. Shimanskaya, Vadim F. Sagach,Paul S. Brookes.
1Anesthesiology, University of Rochester Medical Center,Rochester NY, USA.2Circulatory Physiology Department,Bogomoletz Institute of Physiology, National Academy ofSciences, Kiev 01601, Ukraine.
Abstract
Both mitochondrial permeability transition pore (PTP) opening
and purine signaling are implicated in cardioprotection via is-
chemic preconditioning (IPC). The PTP opening is accomponied
by release of intramitochondrial solutes, and therefore we hy-
pothesized that purine release from mitochondria during PTP
opening may by required for IPC signaling. Herein we show
that upon PTP opening, isolated mitochondria release adenos-
ine, inosine and 3’-ribosyl uric acid monophosphate (3-
RUAMP), and that perfused hearts subject to IPC release
Figure 6. LC-MS analysis of cardiac effluents. Hearts were
subject to IR and cardiac effluents (Figure 2) analyzed by
LC-MS as detailed in the methods. A: UV chromatograms
of effluent from control (upper trace) and IR (lower trace)
hearts. Note y-axes are not the same. B: Retention times,
areas, and identities of the major numbered peaks from traces
in panel A. Identities were based on retention times in UV
and mass chromatograms, and m/z patterns relative to stan-
dards in Figure 4. C-E: Mass spectra of peaks 1, 3 and 4
from panel A. Note the appearance in C and D of species
identified as metabolites of 3-RUAMP (Figure 5D). To
conserve space, spectra for all peaks are not shown. All
data are representative of at least 3 independent experiments
inosine and 3-RUAMP derivatives. Both these events were in-
hibited by the PTP blockers cyclosporin A and sanglifehrin A.
Implications for cardioprotective signaling by purines and the
PTP are discussed.
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