Dataset Information

Mitochondrial dysfunction and calcium deregulation by the RanBP9-cofilin pathway.

ABSTRACT: Mitochondrial dysfunction and synaptic damage are important features of Alzheimer's disease (AD) associated with amyloid ? (A?) 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 A? generation and focal adhesion disruption by accelerating the endocytosis of APP and ?1-integrin, respectively. Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates A?-induced neurotoxicity. Here we show in primary hippocampal neurons that RanBP9 potentiates A?-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 A? 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.

SUBMITTER: Roh SE

PROVIDER: S-EPMC3834781 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Mitochondrial dysfunction and calcium deregulation by the RanBP9-cofilin pathway.

Roh Seung-Eon SE Woo Jung A JA Lakshmana Madepalli K MK Uhlar Courtney C Ankala Vinishaa V Boggess Taylor T Liu Tian T Hong Yun-Hwa YH Mook-Jung Inhee I Kim Sang Jeong SJ Kang David E DE

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130827 12

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 media ...[more]

PMID: 23982146

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Project description:Oxidative stress is one of the main causes of osteoblast apoptosis induced by post-menopausal osteoporosis. The authors previously found that metformin can reverse the loss of bone mass in post-menopausal osteoporosis. The present study aimed to further clarify the effects and mechanisms of action of metformin in post-menopausal osteoporosis under conditions of oxidative stress. Combined with an in-depth investigation using the transcriptome database, the association between oxidative stress and mitochondrial dysfunction in post-menopausal osteoporosis was confirmed. A pre-osteoblast model of oxidative stress was constructed, and the apoptotic rate following the addition of hydrogen peroxide and metformin was detected using CCK-8 assay and Annexin V-FITC/PI staining. Mitochondrial membrane potential was detected using the JC-1 dye, the intracellular calcium concentration was detected using Fluo-4 AM, the intracellular reactive oxygen species (ROS) level was observed using DCFH-DA, and the mitochondrial superoxide level was observed using MitoSOX Red. Bay K8644 was used to increase the level of intracellular calcium. siRNA was used to interfere with the expression of glycogen synthase kinase (GSK)-3β. Western blot analysis was used to detect the expression of mitochondrial dysfunction-related proteins. The results revealed that oxidative stress decreased mitochondrial membrane potential and increased intracellular ROS, mitochondrial superoxide and cytoplasmic calcium levels in pre-osteoblasts; however, metformin improved mitochondrial dysfunction and reversed oxidative stress-induced injury. Metformin inhibited mitochondrial permeability transition pore opening, suppressed the cytoplasmic calcium influx and reversed pre-osteoblast apoptosis by promoting GSK-3β phosphorylation. Moreover, it was found that EGFR was the cell membrane receptor of metformin in pre-osteoblasts, and the EGFR/GSK-3β/calcium axis played a key role in metformin reversing the oxidative stress response of pre-osteoblasts in post-menopausal osteoporosis. On the whole, these findings provide a pharmacological basis for the use of metformin for the treatment of post-menopausal osteoporosis.

Project description:The accumulation of amyloid-β protein (Aβ) is an early event associated with synaptic and mitochondrial damage in Alzheimer's disease (AD). Recent studies have implicated the filamentous actin (F-actin) severing protein, Cofilin, in synaptic remodeling, mitochondrial dysfunction, and AD pathogenesis. However, whether Cofilin is an essential component of the AD pathogenic process and how Aβ impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that Aβ42 oligomers (Aβ42O, amyloid-β protein 1-42 oligomers) bind with high affinity to low or intermediate activation conformers of β1-integrin, resulting in the loss of surface β1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of β1-integrin prevented Aβ42O-induced Cofilin activation, and allosteric modulation or activation of β1-integrin significantly reduced Aβ42O binding to neurons while blocking Aβ42O-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, depletion of F-actin/focal Vinculin, and apoptosis. Cofilin, in turn, was required for Aβ42O-induced loss of cell surface β1-integrin, disruption of F-actin/focal Talin-Vinculin, and depletion of F-actin-associated postsynaptic proteins. SSH1 reduction, which mitigated Cofilin activation, prevented Aβ42O-induced mitochondrial Cofilin translocation and apoptosis, while AD brain mitochondria contained significantly increased activated/oxidized Cofilin. In mechanistic support in vivo, AD mouse model (APP (amyloid precursor protein)/PS1) brains contained increased SSH1/Cofilin and decreased SSH1/14-3-3 complexes, indicative of SSH1-Cofilin activation via release of SSH1 from 14-3-3. Finally, genetic reduction in Cofilin rescued APP/Aβ-induced synaptic protein loss and gliosis in vivo as well as deficits in long-term potentiation (LTP) and contextual memory in APP/PS1 mice. These novel findings therefore implicate the essential involvement of the β1-integrin-SSH1-Cofilin pathway in mitochondrial and synaptic dysfunction in AD.

Dataset Information

Mitochondrial dysfunction and calcium deregulation by the RanBP9-cofilin pathway.

Publications

Mitochondrial dysfunction and calcium deregulation by the RanBP9-cofilin pathway.

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