Ischemia and reperfusion causes severe mitochondrial damage, including swelling and deposits of
hydroxyapatite crystals in the mitochondrial matrix. These crystals are indicative of a massive influx of Ca2+ into the mitochondrial matrix occurring during reoxygenation. We have observed that mitochondria isolated from rat hearts after 90 minutes of
anoxia followed by reoxygenation, show a specific inhibition in the electron transport chain between
NADH dehydrogenase and
ubiquinone in addition to becoming uncoupled (unable to generate
ATP). This inhibition is associated with an increased H2O2 formation at the
NADH dehydrogenase level in the presence of
NADH dependent substrates. Control rat mitochondria exposed for 15 minutes to high Ca2+ (200 nmol/mg
protein) also become uncoupled and electron transport inhibited between
NADH dehydrogenase and
ubiquinone, a lesion similar to that observed in post-ischemic mitochondria. This Ca(2+)-dependent effect is time dependent and may be partially prevented by
albumin, suggesting that it may be due to
phospholipase A2 activation, releasing
fatty acids, leading to both inhibition of electron transport and uncoupling. Addition of arachidonic or
linoleic acids to control rat heart mitochondria, inhibits electron transport between Complex I and III. These results are consistent with the following hypothesis: during
ischemia, the intracellular energy content drops severely, affecting the cytoplasic concentration of
ions such as Na+ and Ca2+. Upon reoxygenation, the mitochondrion is the only organelle capable of eliminating the excess cytoplasmic Ca2+ through an electrogenic process requiring
oxygen (the low
ATP concentration makes other
ATP-dependent Ca2+ transport systems non-operational).(ABSTRACT TRUNCATED AT 250 WORDS)