BNIP3 mediates cell death by different pathways following localization to endoplasmic reticulum and mitochondrion
AUTOR(ES)
Zhang, Lu
FONTE
The Federation of American Societies for Experimental Biology
RESUMO
BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) is a BH3-only proapoptotic member of the Bcl-2 family. Because the interaction of Bcl-2 proteins with intracellular Ca2+ stores has been linked to apoptosis, the role of Ca2+ transfer between endoplasmic reticulum (ER) and mitochondria in BNIP3-mediated cell death was determined in a rat dopaminergic neuronal cell line, Mes 23.5. BNIP3 mutants were constructed to target either ER or mitochondria. Localization of BNIP3 to the ER membrane facilitated release of Ca2+ and subsequently increased uptake of Ca2+ into mitochondria. Excessive accumulation of mitochondrial Ca2+ decreased mitochondrial membrane potential (ΔΨm), resulting in execution of a caspase-independent cell death. Reduction of ER Ca2+ induced by ER-targeted BNIP3 and the subsequent cell death was blocked by the antiapoptotic protein, Bcl-2. On the other hand, mitochondria-targeted BNIP3 initiated apoptosis by a Ca2+-independent mechanism by inducing mitochondrial pore transition and dissipation of ΔΨm. The disruption of ΔΨm and cell death was not blocked by Bcl-2 overexpression. These findings show that BNIP3 undergoes a dual subcellular localization and initiates different cell death signaling events in the ER and mitochondria. Bcl-2 counters the BNIP3-initiated mobilization of ER Ca2+ depletion to reduce the level of apoptosis.—Zhang, L., Li, L., Liu, H., Borowitz, J. L., Isom, G. E. BNIP3 mediates cell death by different pathways following localization to endoplasmic reticulum and mitochondrion.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2747673Documentos Relacionados
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