Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury

Abstract

Acute ischemic and brain injury is triggered by excitotoxic elevation of intraneuronal Ca 2+ followed by reoxygenation-dependent oxidative stress, metabolic failure, and cell death. Studies performed in vitro with neurons exposed to excitotoxic concentrations of glutamate demonstrate an initial rise in cytosolic [Ca 2+], followed by a reduction to a normal, albeit slightly elevated concentration. This reduction in cytosolic [Ca 2+] is due partially to active, respiration-dependent mitochondrial Ca 2+ sequestration. Within minutes to an hour following the initial Ca 2+ transient, most neurons undergo delayed Ca 2+ deregulation characterized by a dramatic rise in cytosolic Ca 2+. This prelethal secondary rise in Ca 2+ is due to influx across the plasma membrane but is dependent on the initial mitochondrial Ca 2+ uptake and associated oxidative stress. Mitochondrial Ca 2+ uptake can stimulate the net production of reactive oxygen species (ROS) through activation of the membrane permeability transition, release of cytochrome c, respiratory inhibition, release of pyridine nucleotides, and loss of intramitochondrial glutathione necessary for detoxification of peroxides. Targets of mitochondrially derived ROS may include plasma membrane Ca 2+ channels that mediate excitotoxic delayed Ca 2+ deregulation.