l-β-ODAP alters mitochondrial Ca2+ handling as an early event in excitotoxicity

Abstract The neurotoxin β-N-oxalyl- l -α,β-diaminopropionic acid ( l -β-ODAP) is an l -glutamate analogue at α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors in neurons and therefore acts as an excitotoxic substance. Chronic exposure to l -β-ODAP present in Lathyrus sativus L. ( L. sativus ) seeds is proposed as the cause of the neurodegenerative disease neurolathyrism, but the mechanism of its action has not been conclusively identified. A key factor in excitotoxic neuronal cell death is a disturbance of the intracellular Ca 2+ homeostasis, including changes in the capacity of intracellular Ca 2+ stores like the endoplasmic reticulum (ER) or mitochondria. In this study, aequorin and other Ca 2+ indicators were used in N2a neuroblastoma cells to investigate alterations of cellular Ca 2+ handling after 24 h exposure to l -β-ODAP. Our data demonstrate increased mitochondrial Ca 2+ loading and hyperpolarization of the mitochondrial membrane potential ( Ψ m ), which was specific for l -β-ODAP and not observed with l -glutamate. We conclude that l -β-ODAP disturbs the ER–mitochondrial Ca 2+ signaling axis and thereby renders the cells more vulnerable to its excitotoxic effects that ultimately will lead to cell death.