Abstract 19824: Molecular Regulation of Novel Pro-survival Bnip3 Spliced Variant Niplet in Cardiac Myocytes Functionally Couples Er and Mitochondria
Alternative splicing provides a versatile mechanism by which cells generate proteins with different or even antagonistic properties. Herein we describe a novel splice variant of the hypoxia-inducible death gene Bnip3. Sequence analysis of the new Bnip3 protein revealed an N-terminus that was identical to Bnip3 but contained an ER retention motif within the C-terminus, therefore we designated the new Bnip3 isoform NIPLET for (Nip-Like ER Target). While Bnip3 was predominately localized to mitochondria and promoted mitochondrial perturbations and necrosis, NIPLET was preferentially localized to the ER and opposed the cytotoxic actions of Bnip3. Interestingly, NIPLET suppressed inter-organelle calcium transfer between ER and mitochondria and mitochondrial permeability transition pore opening by a mechanism dependent upon the dynamin motor protein Mitofusin-2 (MFN2). Notably, NIPLET mutations within in the critical ER retention motif rendered NIPLET defective for interacting with MFN2 and suppression of necrosis induced by Bnip3 or hypoxia. Hence, our findings reveal a novel signaling pathway that functionally couples ER and mitochondria for cell survival to a mechanism that is mutually dependent and obligatorily linked to a novel BNIP3 protein in cardiac myocytes.
Author Disclosures: J. Lin: None. H. Gang: None. R. Dhingra: None.
- © 2015 by American Heart Association, Inc.