Mitochondrial DNA in the placenta and maternal blood in PE and FGR

Mitochondria have an array of function fundamental for cell survival, including the generation of ATP, synthesis of proteins, lipids, steroids, and regulation of programmed cell death. Moreover, they are considered the powerhouse of the cell, as they consume oxygen and produce ATP across the respiratory chain complexes. During this process, a physiological production of reactive oxygen species (ROS) occurs. However, if ROS are not correctly inactivated by endogenous enzymes, oxidative stress is generated. Interestingly, the mitochondrion has its own genome, independent to the nuclear genome. It consists of circular molecules of DNA (mtDNA) containing 37 genes. Each mitochondrion contains several copies of mtDNA. The number of mtDNA copies depends on the cell type. mtDNA is especially sensitive to oxidative stress and is more prone to damage than nuclear DNA since compared to nuclear DNA, mtDNA lacks histone proteins and introns and has lower DNA repair activity. In addition, it has been suggested that mitochondria compensate for mtDNA oxidative damage by increasing mtDNA content, hence mtDNA content has been suggested as a marker of mitochondrial response to damage. Mitochondria are therefore considered “sensors” of the surrounding environment. As mitochondria have an array of roles within the placenta, placental mitochondria must adapt to different demands changes in the energetic demands throughout gestation, by varying their number and activity. The reduced placental perfusion and oxidative stress characterizing the intrauterine environment of fetal growth restriction (FGR) and preeclampsia (PE) may therefore affect mitochondrial content and function. Thus, studying mitochondria in placenta or maternal blood can give interesting information on the pathophysiology of these pathologies and representing possible biomarkers for diagnosis. Indeed, multiple studies of PE and FGR have shown increases in placental mitochondrial content, indicating that placental mitochondrial biogenesis is initiated in reaction to adverse conditions. Mt altered oxygen consumption has also be shown in FGR and PE placentas. In maternal blood of FGR pregnancies at third trimester, mtDNA levels were also increased compared to normal pregnancies. However, mtDNA copy number in peripheral blood at first trimester of patients who later developed PE, has been recently shown to be significantly lower in both early- and late-onset PE when compared controls, thus suggesting that the compensatory mt response to cellular stress can lead to the accumulation of mtDNA in peripheral blood that reaches the highest levels at the end of gestation. On the contrary, the initial decrease in mtDNA might represent the impaired energetic status of placentas that later will develop PE. In conclusion, FGR and PE are associated with alterations in placental/blood mitochondrial content and function, but damage and adaptive responses vary in different studies depending on several possible reasons (e.g.: different severity or timing of the insult, gestational age, Different inclusion/exclusion criteria and different clinical protocols in nutritional and lifestyle advice. Understanding mt alterations is crucial for the identification of mechanisms regulating placental development during a complicated pregnancy. The better understanding of mitochondrial content, structure and function in the placenta provides an opportunity to explore interventional avenues and might open new perspectives for therapeutic future developments.