Bnip3 mediates permeabilization of mitochondria and release of cytochrome c via a novel mechanism
| Autor: | M. Richard Sayen, Jeffery D. Molkentin, Roberta A. Gottlieb, Youngil Lee, Shivaji Rikka, Melissa N. Quinsay, Åsa B. Gustafsson |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Mice Transgenic Mitochondrion Biology Mitochondrial apoptosis-induced channel Article Mitochondrial Proteins Rats Sprague-Dawley Mice Proto-Oncogene Proteins Animals Molecular Biology Cell Death Cytochrome c Bcl-2 family Cytochromes c Membrane Proteins Fibroblasts Fluoresceins Recombinant Proteins Cell biology Mitochondria Rats Microscopy Electron Cross-Linking Reagents Membrane protein Mitochondrial permeability transition pore Mitochondrial matrix Apoptosis biology.protein Cardiology and Cardiovascular Medicine |
| Zdroj: | Journal of molecular and cellular cardiology. 48(6) |
| ISSN: | 1095-8584 |
| Popis: | Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with loss of cardiac myocytes after a myocardial infarction. Previous studies have demonstrated that Bnip3 induces mitochondrial dysfunction, but the mechanisms involved in this process remain unknown. In this study, we demonstrate that Bnip3 induces permeabilization of the mitochondria via a novel mechanism that is different from other BH3-only proteins. We found that Bnip3 induced mitochondrial swelling and cytochrome c release in isolated heart mitochondria in vitro. Another BH3-only protein, tBid, also caused release of cytochrome c but failed to induce swelling of mitochondria. Swelling of mitochondria is a characteristic of mitochondrial permeability transition pore (mPTP) opening, but Bnip3-mediated mitochondrial swelling was insensitive to cyclosporine A, an inhibitor of the mPTP and independent of cyclophilin D (cypD), an essential component of the mPTP. Bnip3 also induced permeabilization of the mitochondrial membranes as evident by calcein release from the matrix in both wild type (WT) and cypD deficient mouse embryonic fibroblasts (MEFs). Moreover, Bnip3 induced mitochondrial matrix remodeling and large amplitude swelling of the inner membrane, which led to disassembly of OPA1 complexes and release from the mitochondria. Thus, these studies suggest that Bnip3 mediates mitochondrial permeabilization by a novel mechanism that is different from other BH3-only proteins. |
| Databáze: | OpenAIRE |
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