Title: G37R SOD1 mutant alters mitochondrial complex I activity, Ca(2+) uptake and ATP production
Authors: Coussee, Evelyne
De Smet, Patrick
Bogaert, Elke
Elens, Iris
Van Damme, Philip
Willems, Peter
Koopman, Werner
Van Den Bosch, Ludo
Callewaert, Geert # ×
Issue Date: Apr-2011
Publisher: Elsevier
Series Title: Cell Calcium vol:49 issue:4 pages:217-225
Abstract: 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: 0143-4160
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group Experimental Neurology
Faculty of Medicine, Campus Kulak Kortrijk
Laboratory for Neurobiology
× corresponding author
# (joint) last author

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