Suppression of mitochondrial electron transport chain function in the hypoxic human placenta: a role for miRNA-210 and protein synthesis inhibition

• Published in: PloS one 2013-01, Vol.8 (1), p.e55194-e55194
• Main Authors: Colleoni, Francesca, Padmanabhan, Nisha, Yung, Hong-Wa, Watson, Erica D, Cetin, Irene, Tissot van Patot, Martha C, Burton, Graham J, Murray, Andrew J
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - metabolism; Altitude; Analysis of Variance; Apoptosis; Biology; Blotting, Western; Cancer; Cell Culture Techniques; Cell cycle; Cell Line; Cytochrome; Cytochrome-c oxidase; Electron transport; Electron transport chain; Electron Transport Chain Complex Proteins - antagonists & inhibitors; Electron Transport Complex IV - metabolism; Energy metabolism; Energy Metabolism - physiology; Female; Fetal development; Fetuses; Fibroblasts; High altitude; High-altitude environments; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia - physiopathology; Inhibition; Iron; Iron-Sulfur Proteins - metabolism; Medicine; Membrane Proteins - metabolism; Metabolism; MicroRNA; MicroRNAs; MicroRNAs - metabolism; MicroRNAs - pharmacology; miRNA; Mitochondria; Mitochondrial DNA; Musculoskeletal system; Neurosciences; Nitric oxide; Nutrients; Oxidases; Oxidative stress; Oxygen; Oxygen - metabolism; Physiology; Placenta; Placenta - physiopathology; Preeclampsia; Pregnancy; Protein biosynthesis; Protein synthesis; Proteins; Real-Time Polymerase Chain Reaction; Respiration; Ribonucleic acid; RNA; Rodents; Sea level; Sulfur; Target recognition
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0055194

Fetal growth is critically dependent on energy metabolism in the placenta, which drives active exchange of nutrients. Placental oxygen levels are therefore vital, and chronic hypoxia during pregnancy impairs fetal growth. Here we tested the hypothesis that placental hypoxia alters mitochondrial electron transport chain (ETS) function, and sought to identify underlying mechanisms. We cultured human placental cells under different oxygen concentrations. Mitochondrial respiration was measured, alongside levels of ETS complexes. Additionally, we studied placentas from sea-level and high-altitude pregnancies. After 4 d at 1% O₂ (1.01 KPa), complex I-supported respiration was 57% and 37% lower, in trophoblast-like JEG3 cells and fibroblasts, respectively, compared with controls cultured at 21% O₂ (21.24 KPa); complex IV-supported respiration was 22% and 30% lower. Correspondingly, complex I levels were 45% lower in placentas from high-altitude pregnancies than those from sea-level pregnancies. Expression of HIF-responsive microRNA-210 was increased in hypoxic fibroblasts and high-altitude placentas, whilst expression of its targets, iron-sulfur cluster scaffold (ISCU) and cytochrome c oxidase assembly protein (COX10), decreased. Moreover, protein synthesis inhibition, a feature of the high-altitude placenta, also suppressed ETS complex protein levels. Our results demonstrate that mitochondrial function is altered in hypoxic human placentas, with specific suppression of complexes I and IV compromising energy metabolism and potentially contributing to impaired fetal growth.