PGC-1-Related Coactivator Modulates Mitochondrial-Nuclear Crosstalk through Endogenous Nitric Oxide in a Cellular Model of Oncocytic Thyroid Tumours

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.

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

“…The observed early increase in PPRC1 expression upon initiation of cell growth paralleled nicely the rapid induction of PPRC1 expression observed upon the initiation of growth in cultured human and mouse cells (Vercauteren et al, 2006(Vercauteren et al, , 2009Raharijaona et al, 2009). Nanog and Gata6 are important transcription factors in mouse embryonic differentiation.…”

“…In contrast to PGC-1a and PGC-1b, which show tissue-specific expression and distinct physiological roles in some oxidative tissues (Puigserver et al, 1998;Wu et al, 1999;Lin et al, 2002;Kamei et al, 2003;St-Pierre et al, 2003), PPRC1 appears to have a more ubiquitous expression pattern in adult and embryonic tissues (Andersson and Scarpulla, 2001;Vercauteren et al, 2006Vercauteren et al, , 2008Vercauteren et al, , 2009Raharijaona et al, 2009). The ubiquitous expression pattern suggests a housekeeping role of PPRC1, which may be more universal and important for cell survival.…”

“…Another report using shRNA-mediated PPRC1 knockdown assays indicated that PPRC1 plays a role in the integration of pathways directing mitochondrial respiratory function and cell growth (Vercauteren et al, 2009). Recently, a cell-line model derived from mitochondrial-rich oncocytic thyroid tumors highlighted the role of PPRC1 in rapidly modulating metabolic function in response to cell cycle state (Raharijaona et al, 2009). Taken together, these in vitro studies suggest a global role for PPRC1 in regulating mitochondrial function and cell growth.…”

2-Methoxyestradiol Affects Mitochondrial Biogenesis Pathway and Succinate Dehydrogenase Complex Flavoprotein Subunit A in Osteosarcoma Cancer Cells

“…Previously, our findings have revealed that treatment of osteosarcoma cells with 2-ME at physiological concentrations resulted in significantly lower nuclear NO levels than treatment with 2-ME at pharmacological concentrations (18). Differential effects depending on NO exposure time and concentration have previously been reported (17). In a long-term effect, a NOdependent pathway has been shown to control mitochondrial biogenesis through up-regulating PGC-1α, the crucial regulator of mitochondrial biogenesis (15)(16)(17).…”

“…Clinical analysis of human invasive breast cancers has revealed a strong correlation between PGC-1α expression in invasive cancer cells and the formation of distant metastases, while PGC-1α silencing has suspended their invasive potential and attenuated metastasis (11)(12)(13). Importantly, mitochondrial respiration and mitochondrial biogenesis remain under the strict control of nitric oxide (NO) (14)(15)(16)(17). Furthermore, as indicated by Aquilano and coauthors, the nuclear recruitment of neuronal nitric oxide synthase (nNOS) and generation of NO in the nucleus are mandatory for the induction of the mitochondrial biogenesis pathway (14).…”