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.

Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction

“…Previous studies have demonstrated that the placental transport of amino acids is reduced in human FGR fetuses, and the activity of placental amino transporters, SNAT2, is also reduced in placentae obtained from FGR pregnancies when compared with uncomplicated pregnancies (Glazier et al 1996, Cetin 2003, Mando et al 2014. STAT3 regulation on placental amino acid transport was demonstrated in chorionic villous explants (Jones et al 2009(Jones et al , 2010.…”

Antiretroviral Therapy for Mitochondrial Toxicity in HIV-Infected Pregnant Women

“…The third study [10] reported the mean (SE) maternal mtDNA of 42.66 ± 5.94% and mt proteins of 12.82 ± 5.73%. The mtDNA mean (SD) in the fourth study [11] was reduced by 39.20% ± 2.78%. The last study [12] revealed that the mean (SE) mtDNA/nDNA ratio was reduced by -18.0 ± 6.1.…”

“…The mutations responsible for genetic mitochondrial diseases can be present in both the nuclear or mitochondrial genome [10]. Genetic mitochondrial diseases are already present in 1 in 5000 newborns and 1 in 200 women may carry one of these deleterious mutations [11]. Studies have shown that ART highly increase mitochondrial mutations.…”

Role of Placental Mitochondria in Development of Pre-eclampsia: Focus on Mitochondrial Dynamics, Redox Signaling and Apoptosis

“…Even in normal pregnancies, placental mitochondrial dysfunction was found to increase significantly as pregnancy progresses, suggesting that it may play a role in the normal development and aging of the placenta [5]. Studies that have focused on the mitochondrial apparatus and antioxidant system in PE are very few, despite them being highly interconnected [6].…”