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BNIP3 mediates cell death by different pathways following localization to endoplasmic reticulum and mitochondrion
Author(s) -
Zhang Lu,
Li Li,
Liu Han,
Borowitz Joseph L.,
Isom Gary E.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-124354
Subject(s) - endoplasmic reticulum , microbiology and biotechnology , mitochondrion , programmed cell death , apoptosis , unfolded protein response , intracellular , cell , chemistry , biology , biochemistry
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 BNIP3mediated 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 (ΔΨ m , resulting in execution of a caspaseindependent 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 aCa 2+ ‐independent mechanism by inducing mitochondrial pore transition and dissipation of ΔΨ m . The disruption of 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, 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. FASEB J . 23, 3405–3414 (2009). www.fasebj.org