Simultaneous age‐related depolarization of mitochondrial membrane potential and increased mitochondrial reactive oxygen species production correlate with age‐related glutamate excitotoxicity in rat hippocampal neurons

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Abstract
Mitochondria are implicated in glutamate excitotoxicity by causing bioenergetic collapse, loss of Ca2+homeostasis, and generation of reactive oxygen species (ROS), all of which become increasingly important clinically with age. Little is known about how aging affects the relative importance of mitochondrial membrane potential (ΔΨm) and ROS production. To determine aging affects on ΔΨmand ROS production in individual somal and axonal/dendritic mitochondria, we compared ROS production while simultaneously monitoring ΔΨmbefore and after glutamate treatment of live neurons from embryonic (day 18), middle‐aged (9–12 months), and old (24 months) rats. At rest, old neuronal mitochondria 1) showed a higher rate of ROS production that was particularly strong in axonal/dendritic mitochondria relative to that in middle‐age neurons, 2) were more depolarized in comparison with neurons of other ages, and 3) showed no differences in ROS or ΔΨmas a function of distance from the nucleus. All ΔΨmgrouped into three classes of high (less than –120 mV), medium (–85 to –120 mV), and low (greater than –85 mV) polarization that shifted toward the lower classes with age at rest. Glutamate exposure dramatically depolarized the ΔΨmin parallel with greatly increased ROS production, with a surprising absence of an effect of age or distance from the nucleus on these mitochondrial parameters. These data suggest that old neurons are more susceptible to glutamate excitotoxicity because of an insidious depolarization of ΔΨmand rate of ROS generation at rest that lead to catastrophic failure of phosphorylative and reductive energy supplies under stress.