Impaired mitochondrial fusion, autophagy, biogenesis and dysregulated lipid metabolism is associated with preeclampsia

Abstract

Preeclampsia(PE) is a pregnancy complication that is diagnosed by the new onset of hypertension and proteinuria. The etiology of PE remains unclear; however, growing evidence indicates that mitochondrial impairment contributes to the pathogenesis. Therefore, we aim to investigate the function of mitochondria in the development of PE. The mitochondrial metabolome in preeclamptic (n = 11) and normal (n = 11) placentas were analyzed using Gas chromatography-mass spectrometry (GC-MS). Student's t-tests and receiver operating characteristic (ROC) curves were conducted to determine which mitochondrial metabolites differed significantly between the two groups. The Pathway Activity Profiling (PAPi) R package was used to predict which metabolic pathways were affected by PE. Western blot analysis was performed to identify the candidate proteins which were associated with mitochondrial repair regulation. GC-MS analysis demonstrated that higher levels of 38 metabolites and lower levels of 2 metabolites were observed in the placenta of patients with severe PE (sPE). Five fatty acids had an area under the ROC curve above 90%. Furthermore, we revealed abnormal regulation of mitochondrial dynamics, autophagy, and biogenesis in sPE. Our discoveries indicate that the compromised lipid metabolism in sPE may result from dysfunctional mitochondria, thus revealing new insights into the etiology of the disease.

Application of metabolomics to preeclampsia diagnosis

“…Within this group, 16 studies investigated blood (serum/plasma) (Kenny et al 2005(Kenny et al , 2008(Kenny et al , 2010Odibo et al 2011;Bahado-Singh et al 2012, 2013, 2017a, 2017bSenyavina et al 2013;Austdal et al 2014Austdal et al , 2015aKuc et al 2014;Mukherjee et al 2014;Koster et al 2015;Chen et al 2017) and two of which also evaluated urine (Austdal et al 2014(Austdal et al , 2015a. One study used urine (Diaz et al 2013) and finally four studies used placenta (Jain et al 2004;Dunn et al 2012;Austdal et al 2015b;Zhou et al 2017), one of which assessed placental mitochondria (Zhou et al 2017). The studies in Table 1 are summarized below.…”

“…Because OS is the one of the features of PE and produced by mitochondria, Zhou et al (2017) studied whether alterations in mitochondrial metabolome of placenta may play a role in this disease. They obtained placental tissues after cesarean section from 11 severe PE patients and 11 normotensive pregnancies.…”

“…This metabolite may produce prostaglandins (vasodilators/vasoconstrictors) and leukotrienes (inflammatory mediator). Furthermore, arachidonate promotes apoptosis and its accumulation in mitochondria can damage these organelles, thus resulting in reduced β-oxidation and the accumulation of fatty acids occur (Zhou et al 2017).…”

“…Other polyunsaturated fatty acids such as docosapentaenoate and docosahexaenoate increased in mitochondrial placenta and plasma of PE patients, respectively (Kenny et al 2010;Zhou et al 2017). Reports indicate that these metabolites can inhibit angiogenesis through limiting vascular endothelial growth factor (Tsuji et al 2003;Chao et al 2014).…”

High Plasma Mitochondrial Dna Early in Pregnancy Is a Risk Factor for Development of Preeclampsia.

“…Pregnancy significantly affects function of mitochondria of the placenta up to 11 th gestational week and when maternal blood flow had increased both placental content of mitochondria and mitochondrial respiratory function are increased since the 12 th GW and onward, so metabolic plasticity of placental mitochondria has relevance to placentamediated diseases (7) and growing evidence indicates that mitochondrial impairment may contribute to pathogenesis of PE (8) .…”