Objectives: Fetal growth is critically dependent on energy metabolism in the placenta, with oxidative phosphorylation at the inner mito-chondrial membrane providing the majority of ATP requirements. Oxygen levels in the placenta are therefore vitally important, and studies of high altitude pregnancies have suggested that chronic hypoxia during pregnancy contributes to impaired fetal growth. However, the molecular mechanism by which O2 deficiency might impair growth has not yet been elucidated. Therefore, the aim of this study was to determine the effect of different O2 concentrations on mitochondria in a placental cell line, a primary placental cell culture and intact human placentas. Methods: Human JEG-3 cells (a trophoblast-like cell line) and primary cultures of human placental fibroblasts were grown at 21%, 10% and 1% atmospheric O2 concentrations for 4 days. Mitochondrial O2 consumption was measured using appropriate substrates and inhibitors to investigate the function of complexes I, II and IV of the respiratory chain. In addition, we measured protein levels of complexes I-IV and ATP-synthase by western blotting and mitochondrial DNA (mtDNA) levels by qPCR. Finally, protein levels of complexes I-IV and ATP-synthase were measured in human placentas from pregnancies at sea level and 3100 m. Results: In both JEG3 cells and fibroblasts cultured at 1% O2, mitochondrial respiration via complexes I and IV was impaired, alongside loss of protein levels of complexes I and IV in JEG3 cells, and of complex IV in fibroblasts. No differences in mtDNA levels were measured in either JEG3 cells or fibroblasts at 1% O2. In high altitude placentas, levels of complex I were lower than in sea level placentas of the same gestational age. Conclusion: This study has, for the first time, demonstrated altered mitochondrial function in placental cells in response to hypoxia. Specific changes at complexes I and IV might compromise energy metabolism and thus underlie impaired fetal growth
Hypoxia induces electron transport chain dysfunction in human placental mitochondria / F. Colleoni, H. Yung, N. Padmanabhan, I. Cetin, M. van Patot, G. Burton, A. Murray. - In: PLACENTA. - ISSN 0143-4004. - 32:9(2011), pp. A46-A46. ((Intervento presentato al convegno IFPA Meeting - International Federation of Placenta Associations tenutosi a Oslo nel 2011.
Hypoxia induces electron transport chain dysfunction in human placental mitochondria
I. Cetin;
2011
Abstract
Objectives: Fetal growth is critically dependent on energy metabolism in the placenta, with oxidative phosphorylation at the inner mito-chondrial membrane providing the majority of ATP requirements. Oxygen levels in the placenta are therefore vitally important, and studies of high altitude pregnancies have suggested that chronic hypoxia during pregnancy contributes to impaired fetal growth. However, the molecular mechanism by which O2 deficiency might impair growth has not yet been elucidated. Therefore, the aim of this study was to determine the effect of different O2 concentrations on mitochondria in a placental cell line, a primary placental cell culture and intact human placentas. Methods: Human JEG-3 cells (a trophoblast-like cell line) and primary cultures of human placental fibroblasts were grown at 21%, 10% and 1% atmospheric O2 concentrations for 4 days. Mitochondrial O2 consumption was measured using appropriate substrates and inhibitors to investigate the function of complexes I, II and IV of the respiratory chain. In addition, we measured protein levels of complexes I-IV and ATP-synthase by western blotting and mitochondrial DNA (mtDNA) levels by qPCR. Finally, protein levels of complexes I-IV and ATP-synthase were measured in human placentas from pregnancies at sea level and 3100 m. Results: In both JEG3 cells and fibroblasts cultured at 1% O2, mitochondrial respiration via complexes I and IV was impaired, alongside loss of protein levels of complexes I and IV in JEG3 cells, and of complex IV in fibroblasts. No differences in mtDNA levels were measured in either JEG3 cells or fibroblasts at 1% O2. In high altitude placentas, levels of complex I were lower than in sea level placentas of the same gestational age. Conclusion: This study has, for the first time, demonstrated altered mitochondrial function in placental cells in response to hypoxia. Specific changes at complexes I and IV might compromise energy metabolism and thus underlie impaired fetal growth
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