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SARS-CoV-2 infection has been related to adverse pregnancy outcomes. A placental role in protecting the fetus from SARS-CoV-2 infection has been documented. Nevertheless, it is still unclear how the placenta is affected in SARS-CoV-2 infection. Here we assessed placental mitochondrial (mt) and oxidative features in COVID-19 and healthy mothers. mtDNA levels, DNA oxidative damage, expression levels of genes involved in antioxidant defenses, mitochondrial dynamics and respiratory chain subunits were investigated in placentas from singleton pregnancies of 30 women with SARS-CoV-2 infection during the third trimester (12 asymptomatic, 18 symptomatic) and 16 controls. mtDNA levels decreased in COVID-19 placentas vs. controls and inversely correlated with DNA oxidative damage, which increased in the symptomatic group. Antioxidant gene expressions decreased in SARS-CoV-2 mothers (CAT, GSS). Symptomatic cases also showed a lower expression of respiratory chain (NDUFA9, SDHA, COX4I1) and mt dynamics (DNM1L, FIS1) genes. Alterations in placental mitochondrial features and oxidative balance in COVID-19-affected mothers might be due to the impaired intrauterine environment, generated by systemic viral effects, leading to a negative vicious circle that worsens placental oxidative stress and mitochondrial efficiency. This likely causes cell homeostasis dysregulations, raising the potential of possible long-term effects.

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Obesity is becoming pandemic and is associated with impaired reproductive potential. Oxidative stress, low-grade chronic inflammation and mitochondrial dysfunctions, which characterize obesity, strongly affect oocyte environment and function. Supplementation with antioxidant and anti-inflammatory compounds has been suggested to improve fertility. Here we evaluated the effect of α-lipoic acid and myo-inositol supplementation on the oocyte environment of infertile obese women. Nineteen normal-weight and twenty-three obese women, infertile for non-ovarian reasons, were recruited. For two months before ovarian stimulation, all women received 400 µg/die folic acid, whereas 15 obese were additionally supplemented with 800 mg α-lipoic acid, 2 g myo-inositol/die. Antioxidant capacity was measured in follicular fluid by enzymatic assay; mitochondrial DNA (mtDNA) content and mRNA levels of two respiratory chain subunits were analyzed in granulosa cells by Real-time PCR. Pregnancy rate was similar between normal-weight and treated obese, and lower in untreated obese patients. Supplemented women showed significantly higher antioxidant levels in follicular fluid compared to the two groups taking only folic acid. Conversely, granulosa cells mtDNA content was decreased in treated and higher in untreated obese patients compared to normal-weight women, suggesting mtDNA increases to compensate for oxidative-stress damages. Reduced expression of respiratory subunits in untreated obese may confirm mitochondria impairment. Interestingly, mtDNA levels inversely correlated to both total and metaphase II oocyte number. In this preliminary study, combined supplementation of α-lipoic acid and myo-inositol in infertile obese women was associated with amelioration in the oxidative status of the oocyte environment, possibly contributing to a higher pregnancy rate.

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INTRODUCTION: Intrauterine growth restriction (IUGR) and preeclampsia (PE) are pregnancy disorders characterized by placental insufficiency with oxygen/nutrient restriction and oxidative stress, all influencing mitochondria functionality and number. Moreover, IUGR and PE fetuses are predisposed to diseases later in life, and this might occur through epigenetic alterations. Here we analyze content and methylation of mitochondrial DNA (mtDNA), for the first time in IUGR and PE singleton fetuses, to identify possible alterations in mtDNA levels and/or epigenetic control of mitochondrial loci relevant to replication (D-loop) and functionality (mt-TF/RNR1: protein synthesis, mt-CO1: respiratory chain complex). METHODS: We studied 35 term and 8 preterm control, 31 IUGR, 17 PE/IUGR and 17 PE human singleton pregnancies with elective cesarean delivery. Fetal cord blood was collected and evaluated for biochemical parameters. Extracted DNA was subjected to Real-time PCR to assess mtDNA content and analyzed for D-loop, mt-TF/RNR1 and mt-CO1 methylation by bisulfite conversion and pyrosequencing. RESULTS: mtDNA levels were increased in all pathologic groups compared to controls. Mitochondrial loci showed very low methylation levels in all samples; D-loop methylation was further decreased in the most severe cases and associated to umbilical vein pO2. mt-CO1 methylation levels inversely correlated to mtDNA content. DISCUSSION: Increased mtDNA levels in IUGR, PE/IUGR and PE cord blood may denote a fetal response to placental insufficiency. Hypomethylation of D-loop, mt-TF/RNR1 and mt-CO1 loci confirms their relevance in pregnancy.

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