Molecular Regulation of a Novel Pro-Survival Bnip3 Spliced Variant NIPLET in Cardiac Myocytes Functionally Couples ER and Mitochondria.

Simple item page
dc.contributor.authorLin, Junjun
dc.contributor.examiningcommitteeSingal, Pawan (Physiology and Pathophysiology) Ravandi, Amir (Physiology and Pathophysiology) Dhingra, Sanjiv (Physiology and Pathophysiology) Wigle, Jeffrey (Biochemistry and Medical Genetics)en_US
dc.contributor.supervisorKirshenbaum, Lorrie A. (Physiology and Pathophysiology)en_US
dc.date.accessioned2016-04-13T16:49:06Z
dc.date.available2016-04-13T16:49:06Z
dc.date.issued2015-11en_US
dc.degree.disciplinePhysiology and Pathophysiologyen_US
dc.degree.levelMaster of Science (M.Sc.)en_US
dc.description.abstractAbstract Alternative splicing provides a versatile mechanism by which cells can 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 Endoplasmic reticulum (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 cell death, NIPLET was preferentially localized to the ER and opposed the cytotoxic actions of Bnip3. Interestingly, NIPLET suppressed mitochondrial injury from Bnip3 activation and mitochondrial permeability transition pore opening by a mechanism dependent upon the dynamin motor protein Mitofusin-2 (MFN2). Notably, mutations of NIPLET within the critical ER retention motif rendered NIPLET defective for interacting with MFN2 and suppressed 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.en_US
dc.description.noteMay 2016en_US
dc.identifier.urihttp://hdl.handle.net/1993/31215
dc.language.isoengen_US
dc.publisherCirculationen_US
dc.rightsopen accessen_US
dc.subjectAlternative Splicingen_US
dc.subjectBnip3en_US
dc.subjectMitochondriaen_US
dc.subjectERen_US
dc.subjectMFN2en_US
dc.titleMolecular Regulation of a Novel Pro-Survival Bnip3 Spliced Variant NIPLET in Cardiac Myocytes Functionally Couples ER and Mitochondria.en_US
dc.typemaster thesisen_US
local.subject.manitobayesen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Junjun 7741809 thesis final.pdf
Size:
2.02 MB
Format:
Adobe Portable Document Format
Description:
Main article of M.Sc. thesis
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
2.2 KB
Format:
Item-specific license agreed to upon submission
Description:
Download
Collections
FGS - Electronic Theses and Practica
Manitoba Heritage Theses