Expression of mutant but not wild-type SOD1 in intact neuronal cells induces alterations in mitochondrial complex I activity, calcium signaling, ATP production, and morphology.

Expression of mutant but not wild-type SOD1 in intact neuronal cells induces alterations in mitochondrial complex I activity, calcium signaling, ATP production, and morphology.

FASEB J. 2009 Nov 25;

Authors: Coussee E, Bogaert E, De Smet P, Faes L, D'hooge P, Gomes P, Elens I, Van Damme P, Willems P, Koopman W, Van Den Bosh L, Callewaert G

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu/Zn superoxide dismutase-1 (SOD1) cause familial ALS, but the molecular mechanisms whereby these mutations induce motor neuron death remain controversial. Here, we show that stable overexpression of mutant human SOD1 (G37R), but not wild-type SOD1 (wt-SOD1), in mouse neuroblastoma cells (N2a) results in morphological abnormalities of mitochondria accompanied by several dysfunctions. Activity of the oxidative phosphorylation complex I was significantly reduced in G37R cells. Reduction in complex I activity appeared to correlate with lower mitochondrial membrane potential and reduced levels of cytosolic ATP. Using different chimeric aequorin constructs, we further analyzed the consequences of mitochondrial dysfunction on cellular and organellar Ca(2+) handling. The presence of mutant G37R SOD1 significantly reduced mitochondrial Ca(2+) uptake, leading to elevated cytosolic Ca(2+) signals, whereas the endoplasmatic reticulum Ca(2+) load was not significantly affected. Together, these findings suggest that the mechanism linking mutant G37R SOD1 and ALS involves mitochondrial respiratory chain deficiency resulting in ATP loss and impairment of mitochondrial and cytosolic Ca(2+) homeostasis.-Coussee, E., Bogaert, E., De Smet, P., Faes, L., D'hooge, P., Gomes, P., Elens, I., Van Damme, P., Willems, P., Koopman, W., Van Den Bosch, L., Callewaert, G. Expression of mutant but not wild-type SOD1 in intact neuronal cells induces alterations in mitochondrial complex I activity, calcium signaling, ATP production, and morphology.

PMID: 19940257 [PubMed - as supplied by publisher]

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Posted 27 Nov 2009 4:36 AM by pubmed: neuroblastoma
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