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Mitochondrial Translocation (mitochondrial + translocation)
Selected AbstractsIsolation and expression of a novel mitochondrial septin that interacts with CRMP/CRAM in the developing neuronesGENES TO CELLS, Issue 2 2003Shusuke Takahashi Background: Collapsin response mediator proteins (CRMPs) and CRAM belong to the unc-33 gene family which is implicated in axon guidance and outgrowth during neural development. However, their exact roles remain largely unknown. To understand the molecular basis of CRMP/CRAM function, we have undertaken to identify CRMP/CRAM interacting proteins. Results: We have identified a novel mitochondrial septin (M-septin) as one of the CRMP/CRAM interacting proteins from the developing rat brain. M-septin is a major, alternatively spliced variant of the H5 gene in developing mouse brain and its expression is up-regulated during the neuronal differentiation of embryonal carcinoma P19 cells. In COS-7 cells, M-septin is specifically localized to mitochondria whereas H5 is diffusely distributed to the perinuclear cytoplasm and plasma membranes. In contrast to H5, M-septin induces the mitochondrial translocation of CRAM but not CRMP2. Finally, M-Septin is found to be transiently translocated to mitochondria before the induction of the neurites and then dissociates from the mitochondria after neurite extension in P19 cells. Conclusions: Our results suggest that M-septin has a role which is distinct from H5, and together with CRMP/CRAM, may play an important role in the neuronal differentiation and axon guidance through the control of mitochondrial function. [source] Nerve growth factor blocks thapsigargin-induced apoptosis at the level of the mitochondrion viaregulation of BimJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6a 2008E. Szegezdi Abstract This study examined how the neurotrophin, nerve growth factor (NGF), protects PC12 cells against endoplasmic reticulum (ER) stress-induced apoptosis. ER stress was induced using thapsigargin (TG) that inhibits the sarcoplasmic/ER Ca2+ -ATPase pump (SERCA) and depletes ER Ca2+ stores. NGF pre-treatment inhibited translocation of Bax to the mitochondria, loss of mitochondrial transmembrane potential, cytochrome c release, activation of caspases (,3, ,7 and ,9) and apoptosis induction by TG. Notably, TG also caused a marked induction of Bimel mRNA and protein, and knockdown of Bim with siRNA protected cells against TG-induced apoptosis. NGF delayed the induction and increased the phosphorylation of Bimel. NGF-mediated protection was dependent on phosphatidylinositol-3 kinase (PI3K) signalling since all above apoptotic events, including expression and phosphorylation status of Bimel protein, could be reverted by the PI3K inhibitor LY294002. In contrast, NGF had no effect on the TG-mediated induction of the unfolded protein response (increased expression of Grp78, GADD34, splicing of XBP1 mRNA) or ER stress-associated pro-apoptotic responses (induction of C/EBP homologous protein [CHOP], induction and processing of caspase-12). These data indicate that NGF-mediated protection against ER stress-induced apoptosis occurs at the level of the mitochondria by regulating induction and activation of Bim and mitochondrial translocation of Bax. [source] Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl-2JOURNAL OF PINEAL RESEARCH, Issue 3 2008Flavia Radogna Abstract:, We have recently shown that melatonin antagonizes damage-induced apoptosis by interaction with the MT-1/MT-2 plasma membrane receptors. Here, we show that melatonin interferes with the intrinsic pathway of apoptosis at the mitochondrial level. In response to an apoptogenic stimulus, melatonin allows mitochondrial translocation of the pro-apoptotic protein Bax, but it impairs its activation/dimerization The downstream apoptotic events, i.e. cytochrome c release, caspase 9 and 3 activation and nuclear vesiculation are equally impaired, indicating that melatonin interferes with Bax activation within mitochondria. Interestingly, we found that melatonin induces a strong re-localization of Bcl-2, the main Bax antagonist to mitochondria, suggesting that Bax activation may in fact be antagonized by Bcl-2 at the mitochondrial level. Indeed, we inhibit the melatonin anti-apoptotic effect (i) by silencing Bcl-2 with small interfering RNAs, or with small-molecular inhibitors targeted at the BH3 binding pocket in Bcl-2 (i.e. the one interacting with Bax); and (ii) by inhibiting melatonin-induced Bcl-2 mitochondrial re-localization with the MT1/MT2 receptor antagonist luzindole. This evidence provides a mechanism that may explain how melatonin through interaction with the MT1/MT2 receptors, elicits a pathway that interferes with the Bcl-2 family, thus modulating the cell life/death balance. [source] The structural plasticity of Tom71 for mitochondrial precursor translocationsACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 9 2010Jingzhi Li Mitochondrial precursors are transported through the translocase of the outer membrane (TOM) complex. Tom70/Tom71 is a major surface receptor of the TOM complex for mitochondrial precursors and facilitates Hsp70/Hsp90-escorted precursor translocation into the mitochondrion. Previous structural studies of Tom71 have revealed that it contains an N-terminal and a C-terminal domain and that the two domains may remain in an open conformation when binding to Hsp70/Hsp90. In a newly obtained crystal form of a complex of Tom71 and the Hsp70 C-terminus, the N-terminal domain was found to have rotated about 12° towards the C-terminal domain compared with the previous determined crystal structure of Tom71 in the open conformation. This newly solved structure is defined as the `intermediate conformation'. The domain rearrangements in Tom71 significantly change the surface hydrophobicity and the volume of the precursor-binding pocket. This work suggests that Tom70/Tom71-family members may exhibit structural plasticity from the intermediate conformation to the fully open conformation when complexed with Hsp70/Hsp90. This structural plasticity enables the precursor receptors to accommodate different precursor substrates for mitochondrial translocation. [source] NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathwayCANCER, Issue 14 2009Ayesha B. Alvero MD Abstract BACKGROUND: Resistance to apoptosis is 1 of the key events that confer chemoresistance and is mediated by the overexpression of antiapoptotic proteins, which inhibit caspase activation. The objective of this study was to evaluate whether the activation of an alternative, caspase-independent cell death pathway could promote death in chemoresistant ovarian cancer cells. The authors report the characterization of NV-128 as an inducer of cell death through a caspase-independent pathway. METHODS: Primary cultures of epithelial ovarian cancer (EOC) cells were treated with increasing concentration of NV-128, and the concentration that caused 50% growth inhibition (GI50) was determined using a proprietary assay. Apoptotic proteins were characterized by Western blot analyses, assays that measured caspase activity, immunohistochemistry, and flow cytometry. Protein-protein interactions were determined using immunoprecipitation. In vivo activity was measured in a xenograft mice model. RESULTS: NV-128 was able to induce significant cell death in both paclitaxel-resistant and carboplatin-resistant EOC cells with a GI50 between 1 ,g/mL and 5 ,g/mL. Cell death was characterized by chromatin condensation but was caspase-independent. The activated pathway involved the down-regulation of phosphorylated AKT, phosphorylated mammalian target of rapamycin (mTOR), and phosphorylated ribosomal p70 S6 kinase, and the mitochondrial translocation of beclin-1 followed by nuclear translocation of endonuclease G. CONCLUSIONS: The authors characterized a novel compound, NV-128, which inhibits mTOR and promotes caspase-independent cell death. The current results indicated that inhibition of mTOR may represent a relevant pathway for the induction of cell death in cells resistant to the classic caspase-dependent apoptosis. These findings demonstrate the possibility of using therapeutic drugs, such as NV-128, which may have beneficial effects in patients with chemoresistant ovarian cancer. Cancer 2009. © 2009 American Cancer Society. [source] | |||||||||||||