Inflammatory cytokines increase mitochondrial damage in motoneuronal cells expressing mutant SOD1.
Recent studies indicate that molecular signals from microglia determine disease progression in transgenic mice overexpressing mutant superoxide dismutase (mutSOD1) typical of amyotrophic lateral sclerosis patients and that toxicity of mutSOD1 in motor neurons descends from its tendency to associate with mitochondria. To assess whether the neurotoxicity of mutSOD1 is influenced by signals from glia, we challenged motoneuronal cells overexpressing either wild-type or mutant SOD1 with inflammatory cytokines. We have obtained evidence that combined treatment with tumor necrosis factor alpha and interferon gamma increases the fraction of both wtSOD1 and mutSOD1 associated with mitochondria, but these inflammatory cytokines dramatically alter morphological features and functionality of mitochondria only in cells expressing mutSOD1. As an effect downstream the increase in mitochondria-associated mutSOD1, the ratio between reduced and oxidized glutathione further shifts toward the oxidized form in this compartment and a clear death phenotype is evoked upon treatment with inflammatory cytokines. These results suggest that signals coming from non-neuronal cells contribute to death of motor neurons induced by mutSOD1 through reinforcement of mitochondrial damage.
Ferri
Alberto
A
Ist. di Neuroscienze del CNR, Sez. Psicobiologia e Psicofarmacologia, Rome, Italy. a.ferri@hsantalucia.it
Nencini
Monica
M
Cozzolino
Mauro
M
Carrara
Paolo
P
Moreno
Sandra
S
Carrì
Maria Teresa
MT
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D009046:Motor Neurons / Q000502:physiology* / Q000648:ultrastructure; D050505:Mutant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D050505:Mutant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005978:Glutathione