G37R SOD1 mutant alters mitochondrial complex I activity, Ca(2+) uptake and ATP production

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...

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Bibliographic Details
Published in:Cell calcium (Edinburgh) 2011-04, Vol.49 (4), p.217-225
Main Authors: Coussee, Evelyne, De Smet, Patrick, Bogaert, Elke, Elens, Iris, Van Damme, Philip, Willems, Peter, Koopman, Werner, Van Den Bosch, Ludo, Callewaert, Geert
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Aequorin - pharmacology
Amino Acid Substitution
Amyotrophic Lateral Sclerosis - etiology
Animals
Calcium - metabolism
Cell Line, Tumor
Electron Transport Complex I - metabolism
Humans
Membrane Potential, Mitochondrial
Mice
Mitochondria - metabolism
Mutation
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Superoxide Dismutase-1
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Summary: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 and correlated with lower mitochondrial membrane potential and reduced levels of cytosolic ATP. Using targeted chimeric aequorin we further analyzed the consequences of mitochondrial dysfunction on cellular Ca(2+) handling. Mitochondrial Ca(2+) uptake, elicited by IP(3)-induced Ca(2+) release from endoplasmic reticulum (ER) was significantly reduced in G37R cells, while uptake induced by a brief Ca(2+) pulse was not affected in permeabilized cells. The decreased mitochondrial Ca(2+) uptake resulted in increased cytosolic Ca(2+) transients, whereas ER Ca(2+) load and resting cytosolic Ca(2+) levels were not 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.
ISSN:1532-1991
DOI:10.1016/j.ceca.2011.02.004