کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10926392 | 1091835 | 2011 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
G37R SOD1 mutant alters mitochondrial complex I activity, Ca2+ uptake and ATP production
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
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چکیده انگلیسی
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 Ca2+ handling. Mitochondrial Ca2+ uptake, elicited by IP3-induced Ca2+ release from endoplasmic reticulum (ER) was significantly reduced in G37R cells, while uptake induced by a brief Ca2+ pulse was not affected in permeabilized cells. The decreased mitochondrial Ca2+ uptake resulted in increased cytosolic Ca2+ transients, whereas ER Ca2+ load and resting cytosolic Ca2+ 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 Ca2+ homeostasis.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cell Calcium - Volume 49, Issue 4, April 2011, Pages 217-225
Journal: Cell Calcium - Volume 49, Issue 4, April 2011, Pages 217-225
نویسندگان
Evelyne Coussee, Patrick De Smet, Elke Bogaert, Iris Elens, Philip Van Damme, Peter Willems, Werner Koopman, Ludo Van Den Bosch, Geert Callewaert,