Suppression of Mitochondrial Electron Transport Chain Function in the Hypoxic Human Placenta: A Role for miRNA-210 and Protein Synthesis Inhibition
Open accessAbstract
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.
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Complex I and III are downregulated at the protein level in the placenta at high altitude, which may be interpreted as an adaptation to reduce production of ROS and so limit HIF signaling.
“It is notable that complex I and III are downregulated at the protein level in the placenta at high altitude, which may be interpreted as an adaptation to reduce production of ROS and so limit HIF signaling (121).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [121]
The same high-altitude placentas show a decrease in the complexes of the mitochondrial electron transport chain at the protein, but not mRNA, level, consistent with translational arrest.
“The same placentas also show a decrease in the complexes of the mitochondrial electron transport chain at the protein, but not mRNA, level, consistent with translational arrest (121).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [121]
Treating trophoblast cell lines with salubrinal, an eIF2α-phosphatase inhibitor, is sufficient to lower the complexes under normoxic conditions.
“Indeed, treating trophoblast cell lines with salubrinal, an eIF2α-phosphatase inhibitor, is sufficient to lower the complexes under normoxic conditions (121).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [121]
In the high-altitude human placenta, there is reduced abundance of all four complexes of the mitochondrial electron transport system responsible for oxidative phosphorylation.
“In addition, in the high-altitude human placenta, there is reduced abundance of all four complexes of the mitochondrial electron transport system (ETS) responsible for oxidative phosphorylation (121).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [121]
The complexes of the electron transport chain are reduced in high-altitude placentas, as is the ATP/ADP ratio, suggesting energetic compromise that could adversely affect transport and synthetic activities of the organ.
“Consistent with this action, the complexes are reduced in these high-altitude placentas (121), as is the ATP/ADP ratio (534), suggesting energetic compromise that could adversely affect transport and synthetic activities of the organ.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [121]
MiR-210 is increased in normal placentas from pregnancies at high altitude, and in placentas from pregnancies complicated by pre-eclampsia.
“It is increased in normal placentas from pregnancies at high altitude (121), and in placentas from pregnancies complicated by pre-eclampsia (272, 351, 401, 611).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [121]
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- Authors
- Colleoni, F., Padmanabhan, N., Yung, H.-W., Watson, E. D., Cetin, I., Tissot van Patot, M. C., Burton, G. J., & Murray, A. J.
- Affiliations
- University of Cambridge (GB)
- University of Milan (IT)
- Corresponding author
- Colleoni, Francesca
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-01-30
- Volume
- 8
- Issue
- 1
- Pages
- e55194
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3559344
- OpenAlex
- W2075544588
- Cited by
- 128
- References
- 51
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 7 · 2023: 7 · 2022: 10 · 2021: 18 · 2020: 6 · 2019: 5 · 2018: 13 · 2017: 10 · 2016: 6 · 2015: 11 · 2014: 10 · 2013: 9 · 2012: 1
- FWCI
- 13.42
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-04-04)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Wellcome Trust (084804, 084804/2/08/Z)
- Action Medical Research (SP4545)
- Research Councils UK (SP4545)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
- Keywords
- placental hypoxia, mitochondrial electron transport chain, miR-210, high-altitude pregnancy, fetal growth restriction, mitochondrial respiration, complex I, cytochrome c oxidase, IscU, COX10, protein synthesis inhibition, placental energy metabolism, placental fibroblasts
- MeSH terms
- Altitude, Analysis of Variance, Hypoxia, Cell Line, Electron Transport Complex IV, Energy Metabolism, Female, Humans, Iron-Sulfur Proteins, Membrane Proteins, Oxygen, Placenta, Pregnancy, Blotting, Western, Cell Culture Techniques, Alkyl and Aryl Transferases, MicroRNAs, Electron Transport Chain Complex Proteins, Real-Time Polymerase Chain Reaction
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