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BNIP3 mediates cell death by different pathways following localization to endoplasmic reticulum and mitochondrion

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA

¹ Correspondence: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333, USA. E-mail: geisom{at}purdue.edu

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 (_m), 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 _m. The disruption of _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 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.

Key Words: apoptosis • Bcl-2 • calcium • thapsagargin

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