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.Graphical
Highlights
Preeclampsia (PE) is a pregnancy disorder that occurs in 5–8% of all pregnancies and has potentially devastating consequences for both mother and fetus
In PE placentae, transcript levels of catalase-1 (CAT1) were lower, while mRNA expression levels of CuZnSOD1 and mitochondrial manganese-dependent superoxide dismutase 2 (MnSOD2) were respectively unchanged and significantly higher compared to controls (Fig. 1c)
In addition to these indicators of oxidative stress in PE placentae, both the expression of tumor necrosis factor-α (TNF-α) and the ratio of pro-apoptotic Bcl-2-associated X protein/anti-apoptotic B cell lymphoma 2 (BAX/BCL-2) mRNA expression levels were significantly higher in PE placentae compared to controls (Supplementary Fig. 1b-c)
Summary
Preeclampsia (PE) is a pregnancy disorder that occurs in 5–8% of all pregnancies and has potentially devastating consequences for both mother and fetus. PE is not de novo onset of hypertension and proteinuria after 20 weeks of gestation, but rather a syndrome involving multiple organs resulting in end-organ damage in terms of cardiovascular, respiratory, central nervous, renal, and hepatic systems [2, 3]. Pre-term delivery is often the only definite treatment for PE, which is associated with adverse short- and longterm health outcomes in the offspring including a high prevalence of subsequent endocrine and metabolic diseases in children [4, 5]. The pathophysiology of PE remains enigmatic, and except for delivery, no curative treatment currently exists. The underlying cellular and molecular mechanisms involved remain unknown, it is believed that, as pregnancy progresses, this aberrant placental perfusion induces further damage and elicits oxidative stress in the placenta, which contributes to the ongoing development of the disease [6,7,8]
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