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The Journal of Neuroscience, April 16, 2008, 28(16):4115-4122; doi:10.1523/JNEUROSCI.5308-07.2008

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Neurobiology of Disease
Mitochondrial Dysfunction in SOD1^G93A-Bearing Astrocytes Promotes Motor Neuron Degeneration: Prevention by Mitochondrial-Targeted Antioxidants

Patricia Cassina,^1,3 * Adriana Cassina,^2,3 * Mariana Pehar,⁴ Raquel Castellanos,¹ Mandi Gandelman,^1,5 Andrés de León,^1,5 Kristine M. Robinson,⁷ Ronald P. Mason,⁶ Joseph S. Beckman,⁷ Luis Barbeito,^3,4,5 and Rafael Radi^2,3

¹Departamento de Histología, ²Departamento de Bioquímica, and ³Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay, ⁴Instituto de Investigaciones Biológicas Clemente Estable, 11600 Montevideo, Uruguay, ⁵Neurodegeneration Laboratory, Institut Pasteur, 11400 Montevideo, Uruguay, ⁶Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina 27709, and ⁷Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331

Correspondence should be addressed to either of the following: Patricia Cassina, Departamento de Histología, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, 11800 Montevideo, Uruguay, Email: pcassina{at}fmed.edu.uy; or Rafael Radi, Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, 11800 Montevideo, Uruguay, Email: rradi{at}fmed.edu.uy

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 SOD1^G93A 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 SOD1^G93A astrocytes, suggesting that mitochondrial defects were associated with nitroxidative damage. Furthermore, superoxide radical formation in mitochondria was increased in SOD1^G93A astrocytes. Similar defects were found in mitochondria isolated from the spinal cord of SOD1^G93A 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, SOD1^G93A 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 SOD1^G93A 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.

Key words: mitochondria; ALS; astrocytes; SOD1; free radicals; antioxidants

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Received June 5, 2007; revised Feb. 18, 2008; accepted Feb. 18, 2008.

Correspondence should be addressed to either of the following: Patricia Cassina, Departamento de Histología, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, 11800 Montevideo, Uruguay, Email: pcassina{at}fmed.edu.uy; or Rafael Radi, Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avenida General Flores 2125, 11800 Montevideo, Uruguay, Email: rradi{at}fmed.edu.uy

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