PP053. The role of peroxisome proliferator-activated receptor gamma co-activator 1-alpha in pregnancy

Delany, Aoife C; McCarthy, Fergus P.; Walsh, Sarah; Kenny, Louise C.

doi:10.1016/j.preghy.2013.04.080

Cited by 5 publications

(4 citation statements)

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“…It may be possible that PGC-1α has a key role in the imbalance of angiogenic factors observed in pre-eclampsia. Delany and colleagues suggested that PGC-1α may be implicated in the pathogenesis of pre-eclampsia (Delany et al 2013 ). Vishnyakova et al found increased placental mitochondrial content in early-onset but not late-onset pre-eclampsia, suggesting that the different pathophysiology leads to differences in mitochondrial response (Vishnyakova et al 2016 ).…”

Section: Discussionmentioning

confidence: 99%

The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats

Mahmoud

Abdel-Aziz

Khafaga

et al. 2023

Mol Med

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Background Hepatitis C virus (HCV) infection is a global public health problem and Egypt has the highest HCV prevalence worldwide. Hence, global efforts target to eliminate HCV by 2030. Sofosbuvir is a nucleotide analogue inhibitor of HCV polymerase essential for viral replication. Animal studies prove that Sofosbuvir metabolites cross the placenta and are excreted in the milk of nursing animals. We aimed to investigate the possible effects of preconception maternal exposure to Sofosbuvir on mitochondrial biogenesis in prenatal fetal liver, skeletal muscle, and placental tissues. Methods The study was conducted on 20 female albino rats divided into a control group receiving a placebo and an exposed group receiving 4 mg/kg orally/day for 3 months of Sofosbuvir. At the end of the treatment period, pregnancy was induced in both groups by mating with healthy male rats overnight. At gestational day 17, all pregnant female rats were sacrificed. Each fetus was dissected to obtain the fetal liver, skeletal muscle, and placental tissues. Results The results of our study indicated that the exposure of young female rats to Sofosbuvir affects pregnancy outcomes. Fetal liver and muscle showed lower mitochondrial DNA-copy number (mtDNA-CN) by about 24% and 29% respectively, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and its downstream targets; nuclear respiratory factor-1 and mitochondrial transcription factor A. While the placental tissues showed different patterns, particularly elevated in mtDNA-CN by about 43%. Conclusions The study provides preliminary evidence of the detrimental effects of Sofosbuvir on the pregnancy outcomes of the exposed females and may impair the placental and fetal organs’ development. These effects may be mediated through modulating mitochondrial homeostasis and functions.

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Section: Discussionmentioning

confidence: 99%

The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats

Mahmoud

Abdel-Aziz

Khafaga

et al. 2023

Mol Med

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“…Although available evidence is scarce, other studies are in line with these results and showed that in PE placentae, where mitochondrial content was decreased, mRNA expression levels of PGC1-α and NRF1 were also decreased [ 46 , 47 ]. Moreover, placental tissue from a reduced uterine perfusion rat model also showed reductions in PGC-1α protein levels [ 48 ], suggesting that impaired placental perfusion may well be linked to mitochondrial adaptations in PE. However, in our study, NRF1 and ERRα protein levels were significantly higher in PE placentae compared to controls suggesting a potential compensatory cellular response to increased mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 99%

Placental Mitochondrial Abnormalities in Preeclampsia

et al. 2021

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Preeclampsia complicates 5–8% of all pregnancies worldwide, and although its pathophysiology remains obscure, placental oxidative stress and mitochondrial abnormalities are considered to play a key role. Mitochondrial abnormalities in preeclamptic placentae have been described, but the extent to which mitochondrial content and the molecular pathways controlling this (mitochondrial biogenesis and mitophagy) are affected in preeclamptic placentae is unknown. Therefore, in preeclamptic (n = 12) and control (n = 11) placentae, we comprehensively assessed multiple indices of placental antioxidant status, mitochondrial content, mitochondrial biogenesis, mitophagy, and mitochondrial fusion and fission. In addition, we also explored gene expression profiles related to inflammation and apoptosis. Preeclamptic placentae were characterized by higher levels of oxidized glutathione, a higher total antioxidant capacity, and higher mRNA levels of the mitochondrial-located antioxidant enzyme manganese-dependent superoxide dismutase 2 compared to controls. Furthermore, mitochondrial content was significantly lower in preeclamptic placentae, which was accompanied by an increased abundance of key constituents of glycolysis. Moreover, mRNA and protein levels of key molecules involved in the regulation of mitochondrial biogenesis were lower in preeclamptic placentae, while the abundance of constituents of the mitophagy, autophagy, and mitochondrial fission machinery was higher compared to controls. In addition, we found evidence for activation of apoptosis and inflammation in preeclamptic placentae. This study is the first to comprehensively demonstrate abnormalities at the level of the mitochondrion and the molecular pathways controlling mitochondrial content/function in preeclamptic placentae. These aberrations may well contribute to the pathophysiology of preeclampsia by upregulating placental inflammation, oxidative stress, and apoptosis.

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“…We found that elevated maternal T significantly decreased Pgc-1α and Nrf1 expression in the placenta. In line with this observation, reduced placental Pgc-1α expression is noted in rats subjected to reduced uterine perfusion pressure (an animal model of PE) [ 51 ]. Importantly, a reduced expression of PGC-1α and NRF1 is also observed in the placenta of PE and growth-restricted pregnancies, correlating with the reduced mitochondrial content in them [ 47 , 52 ].…”

Section: Discussionmentioning

confidence: 79%

Testosterone Decreases Placental Mitochondrial Content and Cellular Bioenergetics

Mishra

Selvanesan

Kumar

2020

Biology

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Placental mitochondrial dysfunction plays a central role in the pathogenesis of preeclampsia. Since preeclampsia is a hyperandrogenic state, we hypothesized that elevated maternal testosterone levels induce damage to placental mitochondria and decrease bioenergetic profiles. To test this hypothesis, pregnant Sprague–Dawley rats were injected with vehicle or testosterone propionate (0.5 mg/kg/day) from gestation day (GD) 15 to 19. On GD20, the placentas were isolated to assess mitochondrial structure, copy number, ATP/ADP ratio, and biogenesis (Pgc-1α and Nrf1). In addition, in vitro cultures of human trophoblasts (HTR-8/SVneo) were treated with dihydrotestosterone (0.3, 1.0, and 3.0 nM), and bioenergetic profiles using seahorse analyzer were assessed. Testosterone exposure in pregnant rats led to a 2-fold increase in plasma testosterone levels with an associated decrease in placental and fetal weights compared with controls. Elevated maternal testosterone levels induced structural damage to the placental mitochondria and decreased mitochondrial copy number. The ATP/ADP ratio was reduced with a parallel decrease in the mRNA and protein expression of Pgc-1α and Nrf1 in the placenta of testosterone-treated rats compared with controls. In cultured trophoblasts, dihydrotestosterone decreased the mitochondrial copy number and reduced PGC-1α, NRF1 mRNA, and protein levels without altering the expression of mitochondrial fission/fusion genes. Dihydrotestosterone exposure induced significant mitochondrial energy deficits with a dose-dependent decrease in basal respiration, ATP-linked respiration, maximal respiration, and spare respiratory capacity. In summary, our study suggests that the placental mitochondrial dysfunction induced by elevated maternal testosterone might be a potential mechanism linking preeclampsia to feto-placental growth restriction.

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PP053. The role of peroxisome proliferator-activated receptor gamma co-activator 1-alpha in pregnancy

Cited by 5 publications

References 0 publications

The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats

The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats

Placental Mitochondrial Abnormalities in Preeclampsia

Testosterone Decreases Placental Mitochondrial Content and Cellular Bioenergetics

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