Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis

Milena Rizzardini, Monica Lupi, Alessandra Mangolini, Elisabetta Babetto, Paolo Ubezio, Lavinia Cantoni

Research output: Contribution to journalArticle

Abstract

G93A Cu/Zn superoxide dismutase (SOD1), a human mutant SOD1 associated with familial amyotrophic lateral sclerosis, increased the toxicity of the mitochondrial toxin rotenone in the NSC-34 motoneuronal cell line. G93ASOD1 cells died more than untransfected and wild-type SOD1 cells after 6 and 24 h exposure to 12.5 μM rotenone. Biparametric flow cytometry showed that rotenone induced rapid hyperpolarization of mitochondrial membrane potential (ΔΨm) in all the cell lines, followed by depolarization, and then by cell death. However, G93ASOD1 mitochondria were significantly more likely to shift from a hyperpolarized to a depolarized condition, and within the still viable cell population there was a higher proportion with depolarized mitochondria, a condition that can be envisaged as a commitment to cell death. ATP, which is needed to prevent loss of ΔΨm, decreased more rapidly and to a greater extent in rotenone-treated G93ASOD1 cells than in the untransfected and wtSOD1cells. In all the cell lines, 1 h after rotenone exposure, mitochondrial hyperpolarization was accompanied by the formation of a comparable amount of reactive oxygen species. However, G93ASOD1 cells reached the highest reactive oxygen species level since their basal level was higher than in untransfected and wild-type SOD1 cells. Our findings indicate that the mutant protein G93ASOD1 enhances the vulnerability of motor neurons to rotenone by mechanism(s) involving oxidative stress and perturbed mitochondrial homeostasis. This suggests that motor neurons from individuals carrying the mutant G93ASOD1 are at greater risk of death after inhibition of the electron transport chain.

Original languageEnglish
Pages (from-to)465-474
Number of pages10
JournalBrain Research Bulletin
Volume69
Issue number4
DOIs
Publication statusPublished - Apr 28 2006

Keywords

  • Amyotrophic lateral sclerosis
  • Cu/Zn superoxide dismutase
  • Mitochondrial membrane potential
  • Motor neuron(s)
  • Oxidative stress
  • Rotenone

ASJC Scopus subject areas

  • Neuroscience(all)

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