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Mitochondrial dysfunction and calcium deregulation by the RanBP9‐cofilin pathway
Author(s) -
Roh SeungEon,
Woo Jung A.,
Lakshmana Madepalli K.,
Uhlar Courtney,
Ankala Vinishaa,
Boggess Taylor,
Liu Tian,
Hong YunHwa,
MookJung Inhee,
Kim Sang Jeong,
Kang David E.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-234765
Subject(s) - mitochondrion , cofilin , neurodegeneration , microbiology and biotechnology , calcium , uniporter , reactive oxygen species , chemistry , cytosol , biology , biochemistry , medicine , cell , cytoskeleton , actin cytoskeleton , disease , organic chemistry , enzyme
Mitochondrial dysfunction and synaptic damage are important features of Alzheimer's disease (AD) associated with amyloid β (Aβ) and tau. We reported previously that the scaffolding protein RanBP9, which is overall increased in brains of patients with AD and in mutant APP transgenic mice, simultaneously promotes Aβ generation and focal adhesion disruption by accelerating the endocytosis of APP and β1‐integrin, respectively. Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates Aβ‐induced neurotoxicity. Here we show in primary hippocampal neurons that RanBP9 potentiates Aβ‐induced reactive oxygen species (ROS) overproduction, apoptosis, and calcium deregulation. Analyses of calcium‐handling measures demonstrate that RanBP9 selectively delays the clearance of cytosolic Ca 2+ mediated by the mitochondrial calcium uniporter through a process involving the translocation of cofilin into mitochondria and oxidative mechanisms. Further, RanBP9 retards the anterograde axonal transport of mitochondria in primary neurons and decreases synaptic mitochondrial activity in brain. These data indicate that RanBP9, cofilin, and Aβ mimic and potentiate each other to produce mitochondrial dysfunction, ROS overproduction, and calcium deregulation, which leads to neurodegenerative changes reminiscent of those seen in AD.—Roh. S.‐E., Woo, J. A., Lakshmana, M. K., Uhlar, C., Ankala, V., Boggess, T., Liu, T., Hong, Y.‐H., Mook‐Jung, I., Kim, S. J., Kang, D. E., Mitochondrial dysfunction and calcium deregulation by the RanBP9‐cofilin pathway. FASEB J. 27, 4776–4789 (2013). www.fasebj.org