Alterations in c-Myc phenotypes resulting from dynamin-related protein 1 (Drp1)-mediated mitochondrial fission
| Autor: | Eric S. Goetzman, Edward V. Prochownik, Yudong Wang, Donna Beer-Stolz, J. Anthony Graves, Jie Lu, B E Van Houten, Kristi Rothermund, M Sarin, Sunder Sims-Lucas, Yuxun Zhang, F Zhang, Jerry Vockley |
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| Rok vydání: | 2013 |
| Předmět: |
Dynamins
Cancer Research Cell Survival Recombinant Fusion Proteins Immunology Oxidative phosphorylation Mitochondrion Biology Mitochondrial Dynamics Oxidative Phosphorylation Cell Line Proto-Oncogene Proteins c-myc 03 medical and health sciences Cellular and Molecular Neuroscience DNM1L 0302 clinical medicine Adenosine Triphosphate Animals Humans Glycolysis Protein kinase A 030304 developmental biology Cell Proliferation 0303 health sciences apoptosis mitofusins Cell Biology Ribonucleotides glycolysis Aminoimidazole Carboxamide Molecular biology OXPHOS Rats Phenotype Mitochondrial biogenesis mitochondrial fusion Electron Transport Chain Complex Proteins Receptors Estrogen 030220 oncology & carcinogenesis Mitochondrial fission Original Article Warburg effect Reactive Oxygen Species |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | The c-Myc (Myc) oncoprotein regulates numerous phenotypes pertaining to cell mass, survival and metabolism. Glycolysis, oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis are positively controlled by Myc, with myc−/− rat fibroblasts displaying atrophic mitochondria, structural and functional defects in electron transport chain (ETC) components, compromised OXPHOS and ATP depletion. However, while Myc influences mitochondrial structure and function, it is not clear to what extent the reverse is true. To test this, we induced a state of mitochondrial hyper-fission in rat fibroblasts by de-regulating Drp1, a dynamin-like GTPase that participates in the terminal fission process. The mitochondria from these cells showed reduced mass and interconnectivity, a paucity of cristae, a marked reduction in OXPHOS and structural and functional defects in ETC Complexes I and V. High rates of abortive mitochondrial fusion were observed, likely reflecting ongoing, but ultimately futile, attempts to normalize mitochondrial mass. Cellular consequences included reduction of cell volume, ATP depletion and activation of AMP-dependent protein kinase. In response to Myc deregulation, apoptosis was significantly impaired both in the absence and presence of serum, although this could be reversed by increasing ATP levels by pharmacologic means. The current work demonstrates that enforced mitochondrial fission closely recapitulates a state of Myc deficiency and that mitochondrial integrity and function can affect Myc-regulated cellular behaviors. The low intracellular ATP levels that are frequently seen in some tumors as a result of inadequate vascular perfusion could favor tumor survival by countering the pro-apoptotic tendencies of Myc overexpression. |
| Databáze: | OpenAIRE |
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