title: BNIP3 mediates cell death by different pathways following localization to endoplasmic reticulum and mitochondrion.
abstract: 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 Ca(2+) stores has been linked to apoptosis, the role of Ca(2+) 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 Ca(2+) and subsequently increased uptake of Ca(2+) into mitochondria. Excessive accumulation of mitochondrial Ca(2+) decreased mitochondrial membrane potential (DeltaPsi(m)), resulting in execution of a caspase-independent cell death. Reduction of ER Ca(2+) 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 Ca(2+)-independent mechanism by inducing mitochondrial pore transition and dissipation of DeltaPsi(m). The disruption of DeltaPsi(m) 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 Ca(2+) depletion to reduce the level of apoptosis.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Borowitz
authors.forename: Gary E
authors.initials: GE
authors.lastname: Isom
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: C090121:BNIP3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D002118:Calcium