Mitochondrial involvement in nitric oxide-induced cellular death in cortical neurons in culture.
Nitric oxide (NO) is an unstable molecule with physiological and pathological properties. In brain, NO acts as a modulator of neurotransmission as well as a protector against neuronal death from several death stimuli. However, beside this protector effect, high NO concentrations produce neuronal death by a mechanism in which the caspase pathway is implicated. In this work, we demonstrate that in cortical neurons the NO toxicity is mediated by mitochondrial dysfunction. SNAP, an NO donor, induces apoptosis in these cells because it 1) increases the p53 and 2) induces cytochrome c release and activation of caspase-9 and caspase-3. SNAP also induces necrosis, through 1) breakdown of the mitochondrial membrane potential, 2) ATP decrease, 3) ROS formation, and 4) LDH and ATP release, indicative of oxidative stress and death by necrosis. To sum up, in cortical neurons, high NO concentrations produced cellular death by both an apoptotic and a necrotic mechanism in which the mitochondria are implicated.
Figueroa
S
S
Instituto de Bioquímica (Centro Mixto CSIC-UCM), Facultad de Farmacia, Ciudad Universitaria, Madrid, Spain.
Oset-Gasque
M J
MJ
Arce
C
C
Martinez-Honduvilla
C J
CJ
González
M P
MP
D000255:Adenosine Triphosphate / Q000378:metabolism; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D003580:Cytochromes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D007093:Imidazoles / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology*; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000494:pharmacology
D001565:Benzoates; D003580:Cytochromes; D007093:Imidazoles; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; C110881:S-nitro-N-acetylpenicillamine; D016159:Tumor Suppressor Protein p53; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D010396:Penicillamine