Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 19, Pages 7933-7938Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0702683104
Keywords
mitochondria; uncoupling
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Funding
- NIDDK NIH HHS [P30 DK040561, P30 DK040561-12, DK54477, R01 DK060837, R01DK060837, DK61562, R56 DK054477, R01 DK061562, R01 DK054477] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007226, 2-T32-GM07226-27] Funding Source: Medline
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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 1 alpha (PGC-1 alpha) and mitochondrial genes. Cells and animals lacking PGC-1 alpha 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-1 alpha 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-1 alpha 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.
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