L-beta-ODAP alters mitochondrial Ca2+ handling as an early event in excitotoxicity

Van Moorhem, Marijke; Decrock, Elke; Coussee, Evelyne; Faes, Liesbeth; De Vuyst, Elke; Vranckx, Katleen; De Bock, Marijke; Wang, Nan; D'Herde, Katharina; Lambein, Fernand; Callewaert, Geert; Leybaert, Luc

doi:10.1016/j.ceca.2010.01.001

L-beta-ODAP alters mitochondrial Ca2+ handling as an early event in excitotoxicity

Author:

Van Moorhem, Marijke

Decrock, Elke ; Coussee, Evelyne ; Faes, Liesbeth ; De Vuyst, Elke ; Vranckx, Katleen ; De Bock, Marijke ; Wang, Nan ; D'Herde, Katharina ; Lambein, Fernand ; Callewaert, Geert ; Leybaert, Luc

Keywords:

l-beta-odap, calcium, mitochondria, excitotoxicity, n2a neuroblastoma cells, aequorinintroduction, lathyrus-sativus neurotoxin, beta-n-oxalyl-l-alpha,beta-diaminopropionic acid, endoplasmic-reticulum, motor-neurons, complex-i, l-alanine, cells, receptors, inhibition, Science & Technology, Life Sciences & Biomedicine, Cell Biology, L-beta-ODAP, Calcium, Mitochondria, Excitotoxicity, N2a neuroblastoma cells, Aequorinintroduction, BETA-N-OXALYL-L-ALPHA,BETA-DIAMINOPROPIONIC ACID, ENDOPLASMIC-RETICULUM, COMPLEX-I, L-ALANINE, CALCIUM, RECEPTORS, INHIBITION, RELEASE, BRAIN, HOMEOSTASIS, Aequorin, Animals, Calcium Signaling, Cell Death, Cell Line, Tumor, Endoplasmic Reticulum, Glutamic Acid, Homeostasis, Indicators and Reagents, Membrane Potential, Mitochondrial, Mice, Neurotoxins, Time Factors, beta-Alanine, 0601 Biochemistry and Cell Biology, 0606 Physiology, 1116 Medical Physiology, Biochemistry & Molecular Biology, 3101 Biochemistry and cell biology, 3208 Medical physiology

Abstract:

The neurotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (L-beta-ODAP) is an L-glutamate analogue at alpha-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-beta-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 Ca2+ homeostasis, including changes in the capacity of intracellular Ca2+ stores like the endoplasmic reticulum (ER) or mitochondria. In this study, aequorin and other Ca2+. indicators were used in N2a neuroblastoma cells to investigate alterations of cellular Ca2+ handling after 24 h exposure to L-beta-ODAP. Our data demonstrate increased mitochondrial Ca2+ loading and hyperpolarization of the mitochondrial membrane potential (psi m), which was specific for L-beta-ODAP and not observed with L-glutamate. We conclude that L-beta-ODAP disturbs the ER mitochondrial Ca2+ signaling axis and thereby renders the cells more vulnerable to its excitotoxic effects that ultimately will lead to cell death. (C) 2010 Elsevier Ltd. All rights reserved.