Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation
| Autor: | Anya Y. Joyo, Mirko Völkers, Mark A. Sussman, Zeping Wang, Bevan Johnson, Mathias H. Konstandin, Matt Mason, Shabana Din, Peter Erhardt, Nancy S. Magnuson, Christopher T. Cottage, Pearl Quijada |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Dynamins
endocrine system Programmed cell death Mice Transgenic Mitochondrion Biology Mitochondrial apoptosis-induced channel Adenoviridae Mice DNM1L Proto-Oncogene Proteins c-pim-1 hemic and lymphatic diseases Animals Myocytes Cardiac Phosphorylation Multidisciplinary Biological Sciences Molecular biology Mitochondria Rats Cell biology Transport protein Protein Transport Apoptosis DNAJA3 Mitochondrial fission |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:5969-5974 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1213294110 |
| Popis: | Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1- S637 , and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pim-dominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis–dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|