Abstract
BackgroundThe PGC-1 related coactivator (PRC), which shares structural and functional features with PGC-1α, is believed to regulate several metabolic pathways as well as mitochondrial biogenesis. Its involvement in the early programming of cell proliferation suggests the existence of finely regulated crosstalk between mitochondrial functions and the cell cycle status.Methodology/Principal FindingsPRC-regulated pathways were explored in a cell-line model derived from mitochondrial-rich tumours with an essentially oxidative metabolism and specifically high PRC expression. The functional status of mitochondria was compared to the results of microarray analysis under conditions of temporal PRC inhibition. To specify the fine PRC regulation, the expression levels of the genes and proteins involved in the oxidative phosphorylation process were studied by real time quantitative PCR and western blotting. As in earlier studies on PGC-1α, we investigated the role of nitric oxide in PRC-regulated mitochondrial biogenesis and determined its action in the control of the phosphorylation status of the mitogen-activated protein kinase pathway.Conclusion/SignificanceWe found that nitric oxide rapidly influences PRC expression at the transcriptional level. Focusing on mitochondrial energetic metabolism, we observed that PRC differentially controls respiratory chain complexes and coupling efficiency in a time-dependent manner to maintain mitochondrial homeostasis. Our results highlight the key role of PRC in the rapid modulation of metabolic functions in response to the status of the cell cycle.
Highlights
Several essential cellular functions of mitochondria depend on a high degree of functional interaction between the nuclear and mitochondrial genomes
PGC-1 related coactivator (PRC)-Mediated Mitochondrial Biogenesis Depends on the Level of Nitric Oxide Production
Since identical results were obtained with the nitric oxide donor SNAP at concentrations of 50 mM and 100 mM, we considered only those of SNAP at 100 mM, this concentration being likely to produce 100 nM equivalent NO during several hours [20]
Summary
Several essential cellular functions of mitochondria depend on a high degree of functional interaction between the nuclear and mitochondrial genomes. Of the hundred structural subunits that make up the oxidative phosphorylation (OXPHOS) complexes, 13 are encoded by the mitochondrial genome. The mechanisms governing the coordination of the multiple transcription factors involved in mitochondrial biogenesis have been partly explained by the discovery of the PGC-1 coactivator family [1]. Three members of this family – PGC1a, PGC1b and PRC – regulate several functions, including adaptative thermogenesis, glucidic metabolism, fatty acid oxidation and mitochondrial metabolism, via functional interactions with various transcriptional factors. Mitochondrial biogenesis is controlled by PGC mainly through interactions with nuclear respiratory factors, NRF-1 and NRF-2, and may be induced via p38 mitogen-activated protein kinase. Its involvement in the early programming of cell proliferation suggests the existence of finely regulated crosstalk between mitochondrial functions and the cell cycle status
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