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

Fingerprint

Rotenone
Motor Neurons
Cell Line
Reactive Oxygen Species
Mitochondria
Cell Death
Mitochondrial Membrane Potential
Mutant Proteins
Electron Transport
Amyotrophic lateral sclerosis 1
Flow Cytometry
Oxidative Stress
Homeostasis
Adenosine Triphosphate
Population

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis. / Rizzardini, Milena; Lupi, Monica; Mangolini, Alessandra; Babetto, Elisabetta; Ubezio, Paolo; Cantoni, Lavinia.

In: Brain Research Bulletin, Vol. 69, No. 4, 28.04.2006, p. 465-474.

Research output: Contribution to journalArticle

Rizzardini, Milena ; Lupi, Monica ; Mangolini, Alessandra ; Babetto, Elisabetta ; Ubezio, Paolo ; Cantoni, Lavinia. / Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis. In: Brain Research Bulletin. 2006 ; Vol. 69, No. 4. pp. 465-474.
@article{ca570c234f134ff49fe8d7b062244c14,
title = "Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis",
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.",
keywords = "Amyotrophic lateral sclerosis, Cu/Zn superoxide dismutase, Mitochondrial membrane potential, Motor neuron(s), Oxidative stress, Rotenone",
author = "Milena Rizzardini and Monica Lupi and Alessandra Mangolini and Elisabetta Babetto and Paolo Ubezio and Lavinia Cantoni",
year = "2006",
month = "4",
day = "28",
doi = "10.1016/j.brainresbull.2006.02.013",
language = "English",
volume = "69",
pages = "465--474",
journal = "Brain Research Bulletin",
issn = "0361-9230",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis

AU - Rizzardini, Milena

AU - Lupi, Monica

AU - Mangolini, Alessandra

AU - Babetto, Elisabetta

AU - Ubezio, Paolo

AU - Cantoni, Lavinia

PY - 2006/4/28

Y1 - 2006/4/28

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - Cu/Zn superoxide dismutase

KW - Mitochondrial membrane potential

KW - Motor neuron(s)

KW - Oxidative stress

KW - Rotenone

UR - http://www.scopus.com/inward/record.url?scp=33646395389&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646395389&partnerID=8YFLogxK

U2 - 10.1016/j.brainresbull.2006.02.013

DO - 10.1016/j.brainresbull.2006.02.013

M3 - Article

C2 - 16624679

AN - SCOPUS:33646395389

VL - 69

SP - 465

EP - 474

JO - Brain Research Bulletin

JF - Brain Research Bulletin

SN - 0361-9230

IS - 4

ER -