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Int. J. Mol. Sci. 2017, 18(4), 687; doi:10.3390/ijms18040687

Cytosolic BNIP3 Dimer Interacts with Mitochondrial BAX Forming Heterodimers in the Mitochondrial Outer Membrane under Basal Conditions

1
Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany
2
Department of Physics, University of Osnabrück, Barbarastr. 7, 49069 Osnabrück, Germany
3
Biocenter Oulu, University of Oulu, Aapistie 5A, 90220 Oulu, Finland
*
Author to whom correspondence should be addressed.
Academic Editor: Terrence Piva
Received: 21 February 2017 / Revised: 14 March 2017 / Accepted: 20 March 2017 / Published: 23 March 2017
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

The primary function of mitochondria is energy production, a task of particular importance especially for cells with a high energy demand like cardiomyocytes. The B-cell lymphoma (BCL-2) family member BCL-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is linked to mitochondrial targeting after homodimerization, where it functions in inner membrane depolarization and permeabilization of the mitochondrial outer membrane (MOM) mediating cell death. We investigated the basal distribution of cardiac BNIP3 in vivo and its physical interaction with the pro-death protein BCL2 associated X, apoptosis regulator (BAX) and with mitochondria using immunoblot analysis, co-immunoprecipitation, and continuous wave and pulsed electron paramagnetic resonance spectroscopy techniques. We found that BNIP3 is present as a dimer in the cytosol and in the outer membrane of cardiac mitochondria under basal conditions. It forms disulfide-bridged, but mainly non-covalent dimers in the cytosol. Heterodimers with BAX are formed exclusively in the MOM. Furthermore, our results suggest that BNIP3 interacts with the MOM directly via mitochondrial BAX. However, the physical interactions with BAX and the MOM did not affect the membrane potential and cell viability. These findings suggest that another stimulus other than the mere existence of the BNIP3/BAX dimer in the MOM is required to promote BNIP3 cell-death activity; this could be a potential disturbance of the BNIP3 distribution homeostasis, namely in the direction of the mitochondria. View Full-Text
Keywords: BNIP3; BAX; cell death; heterodimerization; homodimerization; mitochondria BNIP3; BAX; cell death; heterodimerization; homodimerization; mitochondria
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Hendgen-Cotta, U.B.; Esfeld, S.; Rudi, K.; Miinalainen, I.; Klare, J.P.; Rassaf, T. Cytosolic BNIP3 Dimer Interacts with Mitochondrial BAX Forming Heterodimers in the Mitochondrial Outer Membrane under Basal Conditions. Int. J. Mol. Sci. 2017, 18, 687.

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