Mitochondrial implications in human pregnancies with intrauterine growth restriction and associated cardiac remodelling

Guitart‐Mampel, Mariona; Juárez‐Flores, Diana Luz; Youssef, L.; Morén, Constanza; García‐Otero, Laura; Roca-Agujetas, Vicente; Catalán-García, Marc; González‐Casacuberta, Ingrid; Tobías, Ester; Milisenda, José C.; Grau, Josep M.; Crispi, F.; Gratacós, Eduard; Cardellach, Francesc; Garrabou, Glòria

doi:10.1111/jcmm.14282

Cited by 20 publications

(15 citation statements)

References 60 publications

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“…Previous studies have suggested that plasma CFCmtDNA and cellular mtDNA copy number reflect different cellular processes in disease conditions. Intracellular mtDNA copy number in PBMCs is thought to reflect variations in mitochondrial bioenergetics and biogenesis 62 , while CFCmtDNA is mostly associated with cellular stress and tissue damage 6 . Here, in addition to plasma CFCmtDNA concentrations, we measured mtDNA copy number in PBMCs.…”

Section: Discussionmentioning

confidence: 99%

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

Cushen

Ricci

et al. 2021

Preprint

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Cell-free circulating mitochondrial DNA (CFCmtDNA) is a damage-associated molecular pattern (DAMP) that can activate Toll-like receptor 9 (TLR-9). The main objectives of this case-control study were 1) to determine absolute concentrations and immunostimulatory capacity of CFCmtDNA, in membrane-bound and -unbound states, in cases with preeclampsia and healthy controls and 2) to implement a bootstrapped penalized regression analysis to establish the contribution of CFCmtDNA to preeclampsia diagnosis and its interaction with commonly collected patient characteristics. To determine the contribution of membrane-bound and -unbound CFCmtDNA in preeclampsia, DNA from plasma samples was exctracted with lysis buffer (membrane-unbound) and without lysis buffer (membrane-bound). CFCmtDNA, quantified using absolute PCR quantification protocol, was reduced in preeclampsia compared to healthy controls (P≤0.02). While the pattern of reduced CFCmtDNA in preeclampsia was similar between methods of DNA extraction, DNA isolation with membrane lysis buffer resulted in 1,000-fold higher CFCmtDNA quantification in the preeclampsia group (P=0.0014) and 430-fold higher CFCmtDNA quantification in the control group (P<0.0001). Even though CFCmtDNA concentrations were reduced, plasma from women with preeclampsia induced greater TLR-9 activation than plasma from gestational age matched controls (P≤0.01) as monitored using SEAP reporter 293 cells expressing human TLR-9. Penalized regression analysis showed that women with preeclampsia are strongly likely to have high concentrations of nDNA and DNase I along with a prior history of preeclampsia. Low concentrations of CFCmtDNA and mode of delivery were also associated with preeclampsia. In conclusion, our data demonstrate increases in the immunostimulatory potential of CFCmtDNA and upregulation of DNA degradation mechanisms in women with preeclampsia at the third trimester.

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Section: Discussionmentioning

confidence: 99%

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

Cushen

Ricci

et al. 2021

Preprint

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“…We found evidence of mitochondrial degeneration, i.e., mitochondrial membrane rupture, absence of mitochondrial ridges and less electron-dense mitochondrial matrix in all treated groups. Placental mitochondrial dysfunction is associated with IUGR (62,63) and may be related, at least in part, to the lower fetal weight observed in high-ZIKV-ICompetent fetuses along with the altered placental apoptotic and proliferative patterns. Furthermore, mitochondrial dysfunction together with ER stress is likely to modify the placental ROS balance and generate local oxidative stress (64), which is associated with impaired fetal development (65).…”

Section: Discussionmentioning

confidence: 99%

ZIKV disrupts placental ultrastructure and drug transporter expression in mice

Andrade

Monteiro

Coelho

et al. 2020

Preprint

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Congenital Zika virus (ZIKV) infection can induce fetal brain abnormalities. Here, we investigated whether maternal ZIKV infection may affect placental physiology and metabolic transport potential, and impact the fetal outcome, regardless of viral presence in the fetus at term. Low (103 PFU-ZIKVPE243; low-ZIKV) and high (5×107 PFU-ZIKVPE243; high-ZIKV) virus titers were injected into immunocompetent (ICompetent C57BL/6) and immunocompromised (ICompromised A129) mice at gestational day (GD)12.5 for tissue collection at GD18.5 (term). High-ZIKV elicited fetal death rates of 66% and 100%, whereas low-ZIKV induced fetal death rates of 0% and 60% in C57BL/6 and A129 dams, respectively. All surviving fetuses exhibited intrauterine growth restriction (IUGR) and decreased placental efficiency. High-ZIKV infection in C57BL/6 and A129 mice resulted in virus detection in maternal spleens and placenta, but only A129 fetuses presented virus RNA in the brains. Nevertheless, pregnancies of both strains produced fetuses with decreased head sizes (p<0.05). Low-ZIKV-A129 dams had higher IL-6 and CXCL1 levels (p<0.05) and their placentas showed increased CCL-2 and CXCL-1 contents (p<0.05). In contrast, low-ZIKV-C57BL/6 dams had an elevated CCL2 serum level, and increased type I and II IFN expression in the placenta. Notably, increased apoptotic rates, less abundant microvilli and mitochondrial degeneration were evidenced in the placental labyrinth (Lz) of ICompromised and high-ZIKV-ICompetent mice, but not in low-ZIKV-C57BL/6. In addition, decreased placental expression of the drug P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and the lipid ABCA1 transporters was detected in all ZIKV-infected groups, but BCRP and ABCA-1 were only reduced in ICompromised and high-ZIKV ICompetent mice. Our data indicate that gestational ZIKV infection triggers specific proinflammatory responses and affects placental turnover and transporter expression, in a way dependent on virus concentration and maternal immune status. Placental damage may impair proper fetal-maternal exchange function and fetal growth/survival, likely contributing to congenital Zika syndrome.

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“…Various ETC complexes as well as their subunits such as Complexes I-IV, cytochrome c oxidase (COX), are found to be downregulated in both preeclamptic and FGR placentas [ 155 , 156 , 157 , 158 ]. Accordingly, activity of one or more of ETC complexes in the placenta is suppressed in preeclampsia and FGR [ 157 , 158 , 159 , 160 , 161 ]. However, the work from Cetin’s laboratory demonstrates that cytotrophoblast ETC activity is increased in placentas of FGR [ 162 ].…”

Section: Mitochondrial Ros and Preeclampsia/fgrmentioning

confidence: 99%

Hypoxia and Mitochondrial Dysfunction in Pregnancy Complications

Zhang

2021

Antioxidants

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Hypoxia is a common and severe stress to an organism’s homeostatic mechanisms, and hypoxia during gestation is associated with significantly increased incidence of maternal complications of preeclampsia, adversely impacting on the fetal development and subsequent risk for cardiovascular and metabolic disease. Human and animal studies have revealed a causative role of increased uterine vascular resistance and placental hypoxia in preeclampsia and fetal/intrauterine growth restriction (FGR/IUGR) associated with gestational hypoxia. Gestational hypoxia has a major effect on mitochondria of uteroplacental cells to overproduce reactive oxygen species (ROS), leading to oxidative stress. Excess mitochondrial ROS in turn cause uteroplacental dysfunction by damaging cellular macromolecules, which underlies the pathogenesis of preeclampsia and FGR. In this article, we review the current understanding of hypoxia-induced mitochondrial ROS and their role in placental dysfunction and the pathogenesis of pregnancy complications. In addition, therapeutic approaches selectively targeting mitochondrial ROS in the placental cells are discussed.

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Mitochondrial implications in human pregnancies with intrauterine growth restriction and associated cardiac remodelling

Cited by 20 publications

References 60 publications

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

ZIKV disrupts placental ultrastructure and drug transporter expression in mice

Hypoxia and Mitochondrial Dysfunction in Pregnancy Complications

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