6-Hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA |
| |
Authors: | Gomez-Lazaro Maria Galindo Maria F Concannon Caoimhín G Segura Miguel F Fernandez-Gomez Francisco J Llecha Nuria Comella Joan X Prehn Jochen H M Jordan Joaquin |
| |
Affiliation: | Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Albacete, Spain; Department of Physiology and RCSI Neuroscience Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland; Cell Signaling and Apoptosis group, Departament de Ciències Mèdiques Bàsiques, Univeristy of Lleida and Hospital Arnau de Vilanova, Lleida, Spain; Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, Lleida, Spain; Centro Regional de Investigaciones Biomedicas, Albacete, Spain |
| |
Abstract: | Mitochondrial alterations have been associated with the cytotoxic effect of 6-hydroxydopamine (6-OHDA), a widely used toxin to study Parkinson's disease. In previous work, we have demonstrated that 6-OHDA increases mitochondrial membrane permeability leading to cytochrome c release, but the precise mechanisms involved in this process remain unknown. Herein we studied the mechanism of increased mitochondrial permeability of SH-SY5Y neuroblastoma cells in response to 6-OHDA. Cytochrome c release induced by 6-OHDA occurred, in both SH-SY5Y cells and primary cultures, in the absence of mitochondrial swelling or a decrease in mitochondrial calcein fluorescence, suggesting little involvement of the mitochondrial permeability transition pore in this process. In contrast, 6-OHDA-induced cell death was associated with a significant translocation of the pro-apoptotic Bax protein from the cytosol to mitochondria and with a significant induction of the BH3-only protein PUMA. Experiments in mouse embryonic fibroblasts deficient in Bax or PUMA demonstrated a role for both proteins in 6-OHDA-induced apoptosis. Although 6-OHDA elevated both total and nuclear p53 protein levels, activation of p53 was not essential for subsequent cell death. In contrast, we found that p38 mitogen-activated protein kinase (MAPK) was activated early during 6-OHDA-induced apoptosis, and that treatment with the p38 MAPK inhibitor SKF86002 potently inhibited PUMA induction, green fluorescent protein-Bax redistribution and apoptosis in response to 6-OHDA. These data demonstrate a critical involvement of p38 MAPK, PUMA, and Bax in 6-OHDA-induced apoptosis. |
| |
Keywords: | BH3 only proteins cell death mitochondrion mitochondrial outer membrane permeability Parkinson's disease permeability transition pore |
本文献已被 PubMed 等数据库收录! |
|