BNIP3 mediates cell death by different pathways following localization to endoplasmic reticulum and mitochondrion.
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.
Zhang
Lu
L
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333, USA.
Li
Li
L
Liu
Han
H
Borowitz
Joseph L
JL
Isom
Gary E
GE
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
C090121:BNIP3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D002118:Calcium