A fundamental system of cellular energy homeostasis regulated by PGC-1α
| Autor: | Marc Uldry, Sibylle Jäger, Christoph Handschin, Lindsay M. Rohas, Bruce M. Spiegelman, Julie St-Pierre |
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| Rok vydání: | 2007 |
| Předmět: |
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Cell Survival Oxidative phosphorylation Mitochondrion AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Calcium in biology Oxidative Phosphorylation chemistry.chemical_compound Mice Adenosine Triphosphate AMP-activated protein kinase Multienzyme Complexes Animals Homeostasis Cyclic AMP Response Element-Binding Protein Promoter Regions Genetic Cells Cultured Multidisciplinary Protein-Serine-Threonine Kinases biology ATP synthase Biological Sciences Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology Mitochondria Biochemistry chemistry biology.protein Trans-Activators Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone Calcium Energy Metabolism Adenosine triphosphate Transcription Factors |
| DOI: | 10.5451/unibas-ep2941 |
| Popis: | Maintenance of ATP levels is a critical feature of all cells. Mitochondria are responsible for most ATP synthesis in eukaryotes. We show here that mammalian cells respond to a partial chemical uncoupling of mitochondrial oxidative phosphorylation with a decrease in ATP levels, which recovers over several hours to control levels. This recovery occurs through an increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (PGC-1alpha) and mitochondrial genes. Cells and animals lacking PGC-1alpha lose this compensatory mechanism and cannot defend their ATP levels or increase mitochondrial gene expression in response to reduced oxidative phosphorylation. The induction of PGC-1alpha and its mitochondrial target genes is triggered by a burst of intracellular calcium, which causes an increase in cAMP-response-element-binding protein and transducer of regulated cAMP-response-element-binding proteins actions on the PGC-1alpha promoter. These data illustrate a fundamental transcriptional cycle that provides homeostatic control of cellular ATP. In light of this compensatory system that limits the toxicity of mild uncoupling, the use of chemical uncoupling of mitochondria as a means of treating obesity should be re-evaluated. |
| Databáze: | OpenAIRE |
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