[Show abstract][Hide abstract] ABSTRACT: Mitochondria are dynamic organelles that change in response to extracellular stimuli. These changes are essential for normal mitochondrial/cellular function and are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Although some molecules have been identified to mediate the mitochondrial fusion and fission process, the underlying mechanisms remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecule that regulates a variety of mitochondrial functions. Here, we examined the role of TRAP1 in the regulation of morphology. Stable TRAP1 knockdown cells showed abnormal mitochondrial morphology, and we observed significant decreases in dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), mitochondrial fission proteins. Similar results were obtained by transient knockdown of TRAP1 in two different cell lines, SH-SY5Y neuroblastoma cells and KNS-42 glioma cells. However, TRAP1 knockdown did not affect expression levels of fusion proteins. The reduction in Drp1 and Mff protein levels was rescued following treatment with the proteasome inhibitor MG132. These results suggest that TRAP1 regulates the expression of fission proteins and controls mitochondrial fusion/fission, which affects mitochondrial/cellular function.
[Show abstract][Hide abstract] ABSTRACT: Repeated stressful events are known to be associated with onset of depression. Further, stress activates the hypothalamic-pituitary-adrenocortical (HPA) system by elevating plasma cortisol levels. However, little is known about the related downstream molecular pathway. In this study, by using repeated water-immersion and restraint stress (WIRS) as a stressor for mice, we attempted to elucidate the molecular pathway induced by elevated plasma corticosterone levels. We observed the following effects both, in vivo and in vitro: (1) repeated exposure to WIRS activates the 3-phosphoinositide-dependent protein kinase (PDK1)-serum glucocorticoid regulated kinase (SGK1)-N-myc downstream-regulated gene 1 (NDRG1)-adhesion molecule (i.e., N-cadherin, α-catenin, and β-catenin) stabilization pathway via an increase in plasma corticosterone levels; (2) the activation of this signaling pathway induces morphological changes in oligodendrocytes; and (3) after recovery from chronic stress, the abnormal arborization of oligodendrocytes and depression-like symptoms return to the control levels. Our data strongly suggest that these abnornalities of oligodendrocytes are possibly related to depression-like symptoms.
[Show abstract][Hide abstract] ABSTRACT: Morphology of primary oligodendrocytes. Morphology of immature (NG2, red) and mature (MBP, green) primary cultured oligodendrocytes after 4 days of differentiation induction.
[Show abstract][Hide abstract] ABSTRACT: Elevation of corticosterone induced by repeated WIRS induce the adherent molecules and morphological change in the oligodendrocytes of corpus callosum via the activation of PDK1-SGK1-NDRG1 pathway.
[Show abstract][Hide abstract] ABSTRACT: Neuronal Sgk1 expression was not affected by acute stress. (A) Sgk1mRNA is expressed in the neurons of CA3 of the hippocampus of the control mice (Cont). However, no increase in Sgk1 mRNA expression was detected in these neurons after repeated WIRS (Stress). (B) Quantification of the results is shown in panel a. These hippocampus Sgk1 mRNA intensities were calculated by using ImageJ software.
[Show abstract][Hide abstract] ABSTRACT: Stress in mitochondria or the endoplasmic reticulum (ER) independently causes cell death. Recently, it was reported that ER stress causes mitochondrial dysfunction via p53-upregulated modulator of apoptosis (PUMA). However, little is known regarding the mitochondria molecules that mediate ER dysfunction. The present study revealed that tumor necrosis factor receptor-associated protein 1 (TRAP1), which localizes in the mitochondria, is associated with the unfolded protein response (UPR) in the ER. TRAP1 knockdown activated the ER-resident caspase-4, which is activated by ER stress, to induce cell death in humans. However, TRAP1 knockdown cells did not show a significant increase in the level of cell death at least within 24 h after early phase of ER stress in comparison with that of the control cells. This finding could be attributed to a number of reasons. TRAP1 knockdown failed to activate caspase-9, which is activated by activated caspase-4. In addition, TRAP1 knockdown increased the basal level of GRP78/BiP expression, which protects cells, and decreased the basal level of C/EBP homologous protein (CHOP) expression, which induces cell death, even under ER stress. Thus, the present study revealed that mitochondria could be a potential regulator of the UPR in the ER through mitochondrial TRAP1.
No preview · Article · Feb 2011 · Neurochemistry International