**10. Oxidative stress increases sensitivity of mitochondria to Ca2+-dependent excitotoxicity**

Increased oxidative stress makes mitochondria more sensitive to the Ca2+-induced permeability transition, which may initiate apoptotic or necrotic cell death (Halestrap et al., 2000; Nicholls, 2008b, 2009). Mitochondria from tgSOD1 animals have high sensitivity to the deleterious effects of calcium (Martin et al., 2009). SCM are particularly sensitive to calcium overload (Sullivan et al., 2004, Panov et al., 2011a). This scenario becomes very likely to occur in tgSOD1 animals in view of the fact that spinal cord tissue contains 8 times more calcium than brain tissue (Panov et al., 2011a). We estimated that when normalized for 1 gram of tissue, BM could sequester several times more Ca2+ than was available in the whole tissue. SCM, on the other hand, could sequester only approximately 20% of the total spinal cord tissue Ca2+ (Panov et al., 2011a). We suggest that the high content of Ca2+ is necessary to hold together the sheets of myelin, which protects the neurons. We have shown recently that increased oxidative stress promotes demyelination in brains of OXYS rats with genetically accelerated aging, which was ameliorated by feeding of animals with malate (Kolosova et al. 2011). Underwood et al. (2010), using magnetic resonance imaging, have shown signs of demyelination in the lumbar spinal cord of ALS-affected SOD1 mice, which were limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were preserved. Damages to myelin sheets of motor neurons may evidently

Role of Neuronal Mitochondrial Metabolic Phenotype in Pathogenesis of ALS 243

Nataliya Kubalik for testing in 2010 the tgSOD1 rats for the time of development of ALS

Abeles, Moshe. *Corticonics: Neural Circuits of the Cerebral Cortex*. Cambridge Univ. Press, 1991

Ahtoniemi, T., Jaronen, M., Keksa-Goldsteine, V., Goldsteins, G., & Koistinaho, J. (2008)

Attwell D., & Laughlin S.B. (2001) An energy budget for signaling in the grey matter of the

Auger, C. & Attwell, D. (2000) Fast removal of synaptic glutamate by postsynaptic

Avossa, D., Grandolfo, M., Mazzarol, F., Zatta, M. & Ballerini, L. (2006) Early signs of

Bacman, S.R., Bradley, W.G. and Moraes, C.T. (2006) Mitochondrial involvement in amyotrophic lateral sclerosis: Trigger or target? *Mol. Neurobiol*. 33 (2), 113-131 Balazs, R. (1965) Control of glutamate metabolism. The effect of pyruvate. *J. Neurochem*. 12,

Balazs R. (1965) Control of glutamate oxidation in brain and liver mitochondrial systems.

Barber, S. C. & Shaw, P.J. (2010) Oxidative stress in ALS: key role in motor neuron injury

Bendotti, C., & Carri, M.T. (2004) Lessons from models of SOD1-linked familial ALS. *Trends* 

Berkich, D. A., Ola, M.S., Cole, J., Sweatt, A.J., Hutson, S.M., & LaNoue, K.F. (2007) Mitochondrial transport proteins of the brain. *J. Neurosci. Res*. 85 (15), 3367-3677 Bertamini, M., Marzani, B., Guarneri, R., Guarneri, P., Bigini, P., Mennini, T. & Curti, D.

Bouteloup, C., Desport, J.C., Clavelou, P., Guy, N., Derumeaux-Burel, H., Ferrier, A. &

Braitenberg, V., & Schüz, A. (1998) *Cortex: statistics and geometry of neuronal connectivity*, 2nd

Brasnjo, G., & Otis, T.S. (2004) Isolation of glutamate transport-coupled charge flux and

Bruijn, L.I., Miller, T.M., & Cleveland, D.W. (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. *Annu. Rev. Neurosci*. 27, 723-749 Damiano, M., Starkov, A.A., Petri, S., Kipiani, K., Kiaei, M., Mattiazzi, M., Beal, F. M., &

mouse central nervous system. *Eur. J. Neurosci*. 16 (12), 2291-2296

(2002) Mitochondrial oxidative metabolism in motor neuron degeneration (mnd)

Couratier, P. (2009) Hypermetabolism in ALS patients: an early and persistent

estimation of glutamate uptake at the climbing fiber-purkinje cell synapse. *Proc.* 

Manfredi, G. (2006) Neural mitochondrial Ca capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. *J.* 

and therapeutic target. *Free Radic. Biol. Med.* 48(5), 629-641

mitochondrial membrane. *Neurobiol. Dis.* 32 (3), 479-485

brain. *J Cereb Blood Flow Metab.* 21, 1133-1145

transporters. *Neuron*. 28 (2), 547-558

Mutant SOD1 from spinal cord of G93A rats is destabilized and binds to inner

motoneuron vulnerability in a disease model system: Characterization of transverse slice cultures of spinal cord isolated from embryonic ALS mice. *Neuroscience*. 138

symptoms.

**14. References** 

ISBN 0521374766

(4), 1179-1194

*Biochem. J*. 95, 497-508

*Mol. Med*. 10 (8), 393-400

ed. Berlin: Springer.

*Neurochem*. 96, 1349-1361

phenomenon. *J. Neurol*. 256 (8), 1236-1242

*Natl. Acad. Sci. USA*. 101, 6273-6278

63-76

release large amounts of calcium. The tissue calcium content in the spinal cord from presymptomatic tgSOD1 rats was diminished by 26% (Panov et al., 2011b). Thus, oxidatively damaged mitochondria may encounter increased amounts of Ca2+ released during demyelination and undergo permeability transition. Halestrap (2005) has pointed out that when mitochondria massively undergo permeability transition, the cells will die by necrosis, which was documented Martin et al.(2009) for ALS animals.
