TY - JOUR
T1 - ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import
AU - Li, Quan
AU - Velde, Christine Vande
AU - Israelson, Adrian
AU - Xie, Jing
AU - Bailey, Aaron O.
AU - Dong, Meng Qui
AU - Chun, Seung Joo
AU - Roy, Tamal
AU - Winer, Leah
AU - Yates, John R.
AU - Capaldi, Roderick A.
AU - Cleveland, Don W.
AU - Miller, Timothy M.
PY - 2010/12/7
Y1 - 2010/12/7
N2 - Mutations in superoxide dismutase 1 (SOD1) cause familial ALS. Mutant SOD1 preferentially associates with the cytoplasmic face of mitochondria from spinal cords of rats and mice expressing SOD1 mutations. Two-dimensional gels and multidimensional liquid chromatography, in combination with tandem mass spectrometry, revealed 33 proteins that were increased and 21 proteins that were decreased in SOD1G93A rat spinal cord mitochondria compared with SOD1WT spinal cord mitochondria. Analysis of this group of proteins revealed a higher-than-expected proportion involved in complex I and protein import pathways. Direct import assays revealed a 30% decrease in protein import only in spinal cord mitochondria, despite an increase in the mitochondrial import components TOM20, TOM22, and TOM40. Recombinant SOD1G93A or SOD1 G85R, but not SOD1WT or a Parkinson's disease-causing, misfolded α-synucleinE46K mutant, decreased protein import by >50% in nontransgenic mitochondria from spinal cord, but not from liver. Thus, altered mitochondrial protein content accompanied by selective decreases in protein import into spinal cord mitochondria comprises part of the mitochondrial damage arising from mutant SOD1.
AB - Mutations in superoxide dismutase 1 (SOD1) cause familial ALS. Mutant SOD1 preferentially associates with the cytoplasmic face of mitochondria from spinal cords of rats and mice expressing SOD1 mutations. Two-dimensional gels and multidimensional liquid chromatography, in combination with tandem mass spectrometry, revealed 33 proteins that were increased and 21 proteins that were decreased in SOD1G93A rat spinal cord mitochondria compared with SOD1WT spinal cord mitochondria. Analysis of this group of proteins revealed a higher-than-expected proportion involved in complex I and protein import pathways. Direct import assays revealed a 30% decrease in protein import only in spinal cord mitochondria, despite an increase in the mitochondrial import components TOM20, TOM22, and TOM40. Recombinant SOD1G93A or SOD1 G85R, but not SOD1WT or a Parkinson's disease-causing, misfolded α-synucleinE46K mutant, decreased protein import by >50% in nontransgenic mitochondria from spinal cord, but not from liver. Thus, altered mitochondrial protein content accompanied by selective decreases in protein import into spinal cord mitochondria comprises part of the mitochondrial damage arising from mutant SOD1.
KW - Amyotrophic
KW - Motor neuron disease
KW - Neurodegenerative disease
KW - Proteomic
UR - http://www.scopus.com/inward/record.url?scp=78650503526&partnerID=8YFLogxK
U2 - 10.1073/pnas.1014862107
DO - 10.1073/pnas.1014862107
M3 - Article
AN - SCOPUS:78650503526
SN - 0027-8424
VL - 107
SP - 21146
EP - 21151
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 49
ER -