Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia
Abstract
Intrauterine growth restriction (IUGR) and pregnancy hypertensive disorders such as preeclampsia (PE) associated with IUGR share a common placental phenotype called "placental insufficiency", originating in early gestation when high availability of energy is required. Here, we assess mitochondrial content and the expression and activity of respiratory chain complexes (RCC) in placental cells of these pathologies. We measured mitochondrial (mt)DNA and nuclear respiratory factor 1 (NRF1) expression in placental tissue and cytotrophoblast cells, gene and protein expressions of RCC (real-time PCR and Western blotting) and their oxygen consumption, using the innovative technique of high-resolution respirometry. We analyzed eight IUGR, six PE, and eight uncomplicated human pregnancies delivered by elective cesarean section. We found lower mRNA levels of complex II, III, and IV in IUGR cytotrophoblast cells but no differences at the protein level, suggesting a posttranscriptional compensatory regulation. mtDNA was increased in IUGR placentas. Both mtDNA and NRF1 expression were instead significantly lower in their isolated cytotrophoblast cells. Finally, cytotrophoblast RCC activity was significantly increased in placentas of IUGR fetuses. No significant differences were found in PE placentas. This study provides genuine new data into the complex physiology of placental oxygenation in IUGR fetuses. The higher mitochondrial content in IUGR placental tissue is reversed in cytotrophoblast cells, which instead present higher mitochondrial functionality. This suggests different mitochondrial content and activity depending on the placental cell lineage. Increased placental oxygen consumption might represent a limiting step in fetal growth restriction, preventing adequate oxygen delivery to the fetus.
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An influx of mitochondrial DNA into the maternal circulation may act as a danger signal/alarmin responsible for the sterile intravascular inflammatory processes of preeclampsia.
“suggesting that an influx of mitochondrial DNA into the maternal circulation may act as a danger signal/alarmin responsible for the sterile (absence of infection) intravascular inflammatory processes of this condition(202, 203)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [203]
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- Authors
- Mandò, C., De Palma, C., Stampalija, T., Anelli, G. M., Figus, M., Novielli, C., Parisi, F., Clementi, E., Ferrazzi, E., & Cetin, I.
- Affiliations
- University of Milan (IT)
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy;
- IRCCS Eugenio Medea (IT)
- Corresponding author
- Cetin, I.
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2014-02-15
- Volume
- 306
- Issue
- 4
- Pages
- E404-E413
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2039792651
- Cited by
- 196
- References
- 61
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 12 · 2023: 22 · 2022: 14 · 2021: 27 · 2020: 23 · 2019: 15 · 2018: 15 · 2017: 12 · 2016: 16 · 2015: 12 · 2014: 8
- FWCI
- 13.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- fetal growth restriction, preeclampsia, placental insufficiency, placental mitochondria, mitochondrial DNA, NRF1, respiratory chain complexes, cytotrophoblast, fetal oxygen delivery, post-transcriptional regulation, hypertensive disorders of pregnancy
- MeSH terms
- Adult, DNA, Mitochondrial, Female, Fetal Growth Retardation, Humans, Infant, Newborn, Mitochondria, Oxygen Consumption, Placenta, Pre-Eclampsia, Pregnancy, Trophoblasts, Nuclear Respiratory Factor 1
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