Placental Mitochondrial Abnormalities in Preeclampsia

Abstract

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.

Vascular Dysfunction in Preeclampsia

“…Though not yet utilized in the clinic, routinely measuring vasopressin during pregnancy is a promising avenue for predicting the future development of preeclampsia and providing more proactive care in these patients [ 171 ]. In terms of molecular targets, less explored areas include the modulation of RGS proteins to mitigate the negative effects of excessive GPCR induction via hormones such as angiotensin II, endothelin-1, and vasopressin [ 213 , 263 ] or the alleviation of cellular stress that leads to mitochondrial dysfunction, cell death, circulating DNA, and subsequent TLR9 activation [ 79 , 83 , 244 , 247 , 252 , 264 , 265 , 266 ]. Though much remains undiscovered, translational research [ 152 , 153 , 154 ], basic animal models [ 155 , 213 , 215 ], and mechanistic cell work [ 56 , 57 , 150 , 213 ] have made a profound impact in the field thus far, and emerging technologies such as trophoblast organoid cultures [ 267 ] provide great potential for new insight.…”

Ultrastructural changes of the placenta in cases of preeclampsia

“…Placental ischemia with OS may aggravate the placental dysfunction and stimulate the placental release of anti-angiogenic mediators. These mediators eventually cause endothelial dysfunction not only in the placenta but also in the kidney with vasoconstriction and hypertension [8,12,24,25].…”

“…PE is a multifactorial disease that develops after 20 weeks of gestation and although the underlying pathophysiology is not clear, abnormal placentation has been suggested. The shallow trophoblast migration towards the uterine spiral arterioles and the impaired remodeling of these arteries leads to a hypoperfused placenta, thus creating a favorable environment for developing hypoxia and oxidative stress (OS) [8,9,10,11].…”

Current Studies of Mitochondrial Quality Control in the Preeclampsia

“…Recent studies have shown decreased protein levels of PGC-1α in PE patients compared with controls (53,55,57), and the transcriptional level of PGC-1α was reduced in pre-term PE and pre-term controls (53) but was not altered between pre-term PE relative to term counterparts (57). All the current studies only assessed the mRNA or protein level of PGC-1α; however, activated PGC-1α (i.e., phosphorylated or deacetylated PGC-1α) has never been reported, and the expression of PGC-1α was not specified in the cytoplasm or mitochondrion.…”