Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: Prevention by mitochondrial-targeted antioxidants

Patricia Cassina, Adriana Cassina, Mariana Pehar, Raquel Castellanos, Mandi Gandelman, Andrés De León, Kristine M. Robinson, Ronald P. Mason, Joseph S. Beckman, Luis Barbeito, Rafael Radi

Resultado de la investigación: Article

199 Citas (Scopus)

Resumen

Mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Recent reports indicate that astrocytes expressing the mutations of superoxide dismutase-1 (SOD1) may contribute to motor neuron injury in ALS. Here,we provide evidence that mitochondrial dysfunction in SOD1G93A rat astrocytes causes astrocytes to induce apoptosis of motor neurons. Mitochondria from SOD1 G93A rat astrocytes displayed a defective respiratory function, including decreased oxygen consumption, lack of ADP-dependent respiratory control, and decreased membrane potential. Protein 3-nitrotyrosine was detected immunochemically in mitochondrial proteins from SOD1G93A astrocytes, suggesting that mitochondrial defects were associated with nitroxidative damage. Furthermore, superoxide radical formation in mitochondria was increased in SOD1G93A astrocytes. Similar defects were found in mitochondria isolated from the spinal cord of SOD1G93A rats, and pretreatment of animals with the spin trap 5,5-dimethyl-1-pyrroline N-oxide restored mitochondrial function, forming adducts with mitochondrial proteins in vivo. As shown previously, SOD1G93A astrocytes induced death of motor neurons in cocultures, compared with nontransgenic ones. This behavior was recapitulated when nontransgenic astrocytes were treated with mitochondrial inhibitors. Remarkably, motor neuron loss was prevented by preincubation of SOD1 G93A astrocytes with antioxidants and nitric oxide synthase inhibitors. In particular, low concentrations (∼10 nM) of two mitochondrial-targeted antioxidants, ubiquinone and carboxy-proxyl nitroxide, each covalently coupled to a triphenylphosphonium cation (Mito-Q and Mito-CP, respectively), prevented mitochondrial dysfunction, reduced superoxide production in SOD1G93A astrocytes, and restored motor neuron survival. Together, our results indicate that mitochondrial dysfunction in astrocytes critically influences motor neuron survival and support the potential pharmacological utility of mitochondrial-targeted antioxidants in ALS treatment.

Idioma originalEnglish
Páginas (desde-hasta)4115-4122
Número de páginas8
PublicaciónJournal of Neuroscience
Volumen28
N.º16
DOI
EstadoPublished - 16 abr 2008

Huella dactilar

Nerve Degeneration
Motor Neurons
Astrocytes
Antioxidants
Amyotrophic Lateral Sclerosis
Mitochondria
Mitochondrial Proteins
Superoxides
Ubiquinone
Coculture Techniques
Oxygen Consumption
Nitric Oxide Synthase
Membrane Potentials
Adenosine Diphosphate
Cations
Spinal Cord
Oxidative Stress
Pharmacology
Apoptosis

ASJC Scopus subject areas

  • Neuroscience(all)

Citar esto

Cassina, Patricia ; Cassina, Adriana ; Pehar, Mariana ; Castellanos, Raquel ; Gandelman, Mandi ; De León, Andrés ; Robinson, Kristine M. ; Mason, Ronald P. ; Beckman, Joseph S. ; Barbeito, Luis ; Radi, Rafael. / Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration : Prevention by mitochondrial-targeted antioxidants. En: Journal of Neuroscience. 2008 ; Vol. 28, N.º 16. pp. 4115-4122.
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title = "Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: Prevention by mitochondrial-targeted antioxidants",
abstract = "Mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Recent reports indicate that astrocytes expressing the mutations of superoxide dismutase-1 (SOD1) may contribute to motor neuron injury in ALS. Here,we provide evidence that mitochondrial dysfunction in SOD1G93A rat astrocytes causes astrocytes to induce apoptosis of motor neurons. Mitochondria from SOD1 G93A rat astrocytes displayed a defective respiratory function, including decreased oxygen consumption, lack of ADP-dependent respiratory control, and decreased membrane potential. Protein 3-nitrotyrosine was detected immunochemically in mitochondrial proteins from SOD1G93A astrocytes, suggesting that mitochondrial defects were associated with nitroxidative damage. Furthermore, superoxide radical formation in mitochondria was increased in SOD1G93A astrocytes. Similar defects were found in mitochondria isolated from the spinal cord of SOD1G93A rats, and pretreatment of animals with the spin trap 5,5-dimethyl-1-pyrroline N-oxide restored mitochondrial function, forming adducts with mitochondrial proteins in vivo. As shown previously, SOD1G93A astrocytes induced death of motor neurons in cocultures, compared with nontransgenic ones. This behavior was recapitulated when nontransgenic astrocytes were treated with mitochondrial inhibitors. Remarkably, motor neuron loss was prevented by preincubation of SOD1 G93A astrocytes with antioxidants and nitric oxide synthase inhibitors. In particular, low concentrations (∼10 nM) of two mitochondrial-targeted antioxidants, ubiquinone and carboxy-proxyl nitroxide, each covalently coupled to a triphenylphosphonium cation (Mito-Q and Mito-CP, respectively), prevented mitochondrial dysfunction, reduced superoxide production in SOD1G93A astrocytes, and restored motor neuron survival. Together, our results indicate that mitochondrial dysfunction in astrocytes critically influences motor neuron survival and support the potential pharmacological utility of mitochondrial-targeted antioxidants in ALS treatment.",
keywords = "ALS, Antioxidants, Astrocytes, Free radicals, Mitochondria, SOD1",
author = "Patricia Cassina and Adriana Cassina and Mariana Pehar and Raquel Castellanos and Mandi Gandelman and {De Le{\'o}n}, Andr{\'e}s and Robinson, {Kristine M.} and Mason, {Ronald P.} and Beckman, {Joseph S.} and Luis Barbeito and Rafael Radi",
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Cassina, P, Cassina, A, Pehar, M, Castellanos, R, Gandelman, M, De León, A, Robinson, KM, Mason, RP, Beckman, JS, Barbeito, L & Radi, R 2008, 'Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: Prevention by mitochondrial-targeted antioxidants', Journal of Neuroscience, vol. 28, n.º 16, pp. 4115-4122. https://doi.org/10.1523/JNEUROSCI.5308-07.2008

Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration : Prevention by mitochondrial-targeted antioxidants. / Cassina, Patricia; Cassina, Adriana; Pehar, Mariana; Castellanos, Raquel; Gandelman, Mandi; De León, Andrés; Robinson, Kristine M.; Mason, Ronald P.; Beckman, Joseph S.; Barbeito, Luis; Radi, Rafael.

En: Journal of Neuroscience, Vol. 28, N.º 16, 16.04.2008, p. 4115-4122.

Resultado de la investigación: Article

TY - JOUR

T1 - Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration

T2 - Prevention by mitochondrial-targeted antioxidants

AU - Cassina, Patricia

AU - Cassina, Adriana

AU - Pehar, Mariana

AU - Castellanos, Raquel

AU - Gandelman, Mandi

AU - De León, Andrés

AU - Robinson, Kristine M.

AU - Mason, Ronald P.

AU - Beckman, Joseph S.

AU - Barbeito, Luis

AU - Radi, Rafael

PY - 2008/4/16

Y1 - 2008/4/16

N2 - Mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Recent reports indicate that astrocytes expressing the mutations of superoxide dismutase-1 (SOD1) may contribute to motor neuron injury in ALS. Here,we provide evidence that mitochondrial dysfunction in SOD1G93A rat astrocytes causes astrocytes to induce apoptosis of motor neurons. Mitochondria from SOD1 G93A rat astrocytes displayed a defective respiratory function, including decreased oxygen consumption, lack of ADP-dependent respiratory control, and decreased membrane potential. Protein 3-nitrotyrosine was detected immunochemically in mitochondrial proteins from SOD1G93A astrocytes, suggesting that mitochondrial defects were associated with nitroxidative damage. Furthermore, superoxide radical formation in mitochondria was increased in SOD1G93A astrocytes. Similar defects were found in mitochondria isolated from the spinal cord of SOD1G93A rats, and pretreatment of animals with the spin trap 5,5-dimethyl-1-pyrroline N-oxide restored mitochondrial function, forming adducts with mitochondrial proteins in vivo. As shown previously, SOD1G93A astrocytes induced death of motor neurons in cocultures, compared with nontransgenic ones. This behavior was recapitulated when nontransgenic astrocytes were treated with mitochondrial inhibitors. Remarkably, motor neuron loss was prevented by preincubation of SOD1 G93A astrocytes with antioxidants and nitric oxide synthase inhibitors. In particular, low concentrations (∼10 nM) of two mitochondrial-targeted antioxidants, ubiquinone and carboxy-proxyl nitroxide, each covalently coupled to a triphenylphosphonium cation (Mito-Q and Mito-CP, respectively), prevented mitochondrial dysfunction, reduced superoxide production in SOD1G93A astrocytes, and restored motor neuron survival. Together, our results indicate that mitochondrial dysfunction in astrocytes critically influences motor neuron survival and support the potential pharmacological utility of mitochondrial-targeted antioxidants in ALS treatment.

AB - Mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Recent reports indicate that astrocytes expressing the mutations of superoxide dismutase-1 (SOD1) may contribute to motor neuron injury in ALS. Here,we provide evidence that mitochondrial dysfunction in SOD1G93A rat astrocytes causes astrocytes to induce apoptosis of motor neurons. Mitochondria from SOD1 G93A rat astrocytes displayed a defective respiratory function, including decreased oxygen consumption, lack of ADP-dependent respiratory control, and decreased membrane potential. Protein 3-nitrotyrosine was detected immunochemically in mitochondrial proteins from SOD1G93A astrocytes, suggesting that mitochondrial defects were associated with nitroxidative damage. Furthermore, superoxide radical formation in mitochondria was increased in SOD1G93A astrocytes. Similar defects were found in mitochondria isolated from the spinal cord of SOD1G93A rats, and pretreatment of animals with the spin trap 5,5-dimethyl-1-pyrroline N-oxide restored mitochondrial function, forming adducts with mitochondrial proteins in vivo. As shown previously, SOD1G93A astrocytes induced death of motor neurons in cocultures, compared with nontransgenic ones. This behavior was recapitulated when nontransgenic astrocytes were treated with mitochondrial inhibitors. Remarkably, motor neuron loss was prevented by preincubation of SOD1 G93A astrocytes with antioxidants and nitric oxide synthase inhibitors. In particular, low concentrations (∼10 nM) of two mitochondrial-targeted antioxidants, ubiquinone and carboxy-proxyl nitroxide, each covalently coupled to a triphenylphosphonium cation (Mito-Q and Mito-CP, respectively), prevented mitochondrial dysfunction, reduced superoxide production in SOD1G93A astrocytes, and restored motor neuron survival. Together, our results indicate that mitochondrial dysfunction in astrocytes critically influences motor neuron survival and support the potential pharmacological utility of mitochondrial-targeted antioxidants in ALS treatment.

KW - ALS

KW - Antioxidants

KW - Astrocytes

KW - Free radicals

KW - Mitochondria

KW - SOD1

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U2 - 10.1523/JNEUROSCI.5308-07.2008

DO - 10.1523/JNEUROSCI.5308-07.2008

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AN - SCOPUS:42949166848

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JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

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