title: The mechanisms of neuronal death produced by mitochondrial toxin 3-nitropropionic acid: the roles of N-methyl-D-aspartate glutamate receptors and mitochondrial calcium overload.
abstract: Previous studies showed that 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase, produced neuronal death secondary to perturbed intracellular calcium homeostasis. However, the response of intramitochondrial calcium ([Ca(2+)](m)) to 3-nitropropionic acid remains unknown. In this study, we investigated the roles of and relationships among [Ca(2+)](m) overload, mitochondrial reactive oxygen species, and mitochondrial membrane depolarization in 3-nitropropionic acid-induced neuronal death. Following 1 mM 3-nitropropionic acid treatment on primary rat neuronal cultures, there was a gradual increase of [Ca(2+)](m) beginning at 2-4 h post 3-nitropropionic acid application, and a twofold increase of mitochondrial reactive oxygen species at 4 h. These were followed by mitochondrial membrane depolarization at 6-8 h post-treatment. By inhibiting [Ca(2+)](m) uptake, Ruthenium Red attenuated the production of reactive oxygen species, and prevented the 3-nitropropionic acid-induced mitochondrial membrane depolarization and 70% of apoptotic neuronal death (P<0.001). Inhibition of caspase activation attenuated the elevation of [Ca(2+)](m) (P<0.001), indicating that caspase activation plays a role in the elevation of [Ca(2+)](m). MK-801, an antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors, prevented 3-nitropropionic acid-induced [Ca(2+)](m) elevation, caspase-3 activation, mitochondrial depolarization, and neuronal death. We conclude that the activation of NMDA glutamate receptor contributes to mitochondrial alterations induced by 3-nitropropionic acid. Inhibition of its activation and [Ca(2+)](m) overload with subsequent mitochondrial membrane depolarization can therefore attenuate the neuronal death induced by 3-nitropropionic acid.
authors.affiliation: Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: W T
authors.initials: WT
authors.lastname: Lee
authors.forename: H S
authors.initials: HS
authors.lastname: Yin
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Shen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D004594:Electrophysiology; D004622:Embryo, Mammalian; D007425:Intracellular Membranes / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds; D009994:Osmolar Concentration; D010539:Permeability; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
chemical_list: D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C015392:3-nitropropionic acid; D002118:Calcium