MIR-210 modulates mitochondrial respiration in placenta with preeclampsia

Abstract

Preeclampsia (PE) affects 5–8% of all pregnancies and is associated with significant maternal and fetal morbidity and mortality. Placental mitochondrial dysfunction has been reported in PE. MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression through mRNA degradation and translational repression. MiR-210 has been previously shown to be up regulated in placentas from pregnancies complicated by PE. We hypothesized that placental mitochondrial dysfunction during PE can be mediated by miR-210. Placentas were collected at term from normotensive pregnancies (CTRL) and those complicated by severe PE (n=6 each) following c-section (no labor). Villous tissue from PE showed significantly increased levels of HIF-1α compared to CTRL with no change in corresponding mRNA expression but with reduced DNA-binding activity. Mitochondrial complex III was significantly decreased in PE along with significantly reduced protein expression in complex I and IV during PE. Among the four miRNAs tested, miR-210 showed significant up regulation in PE and significant down regulation of its target, ISCU mRNA. To understand the role of miR-210 in PE, loss- and gain-of-function studies were performed using primary trophoblasts. Trophoblasts were transfected with miR-210 inhibitor or pre-miR-210 and mitochondrial function was measured using Seahorse Extracellular Flux Analyzer. Cells transfected with pre-miR-210 showed significant reduction in oxygen consumption. In contrast, transfection of trophoblast with AntagomiR-210 was sufficient to prevent the DFO-mediated respiratory deficiency. These data collectively suggest that miR-210 over expression during PE could be responsible for placental mitochondria dysfunction.

Dysregulated circulating miRNAs in preeclampsia

“…Notably, miR-210, which is one of the more commonly recurring miRNAs overexpressed in PE (22,(32)(33)(34)(35)(36), was also elevated in our PE cohort. This particular miR-210 has been identified as a hypoxia-induced miRNA in many cell types and tissues and is consistently upregulated by hypoxia in both physiological and malignant conditions (37,38).…”

Variations of MicroRNAs in Human Placentas and Plasma From Preeclamptic Pregnancy

“…Some of our data are consistent with other reports, such as the downregulation of miR-18a, miR-195, miR-223, and miR-411, 8,11 and the upregulation of miR-30a-3p, miR-193b, miR-210, and miR-518b in preeclamptic placentas. [7][8][9][10][11][12]21,22 Meanwhile, for the first time to our knowledge, several miRNAs (miR-17, miR-17-3p, miR-19b1, miR-92a1, miR-379, miR-524, miR-151, miR-218) were found to be aberrantly expressed in sPE placentas.To date, several studies have shown aberrant miRNA profiles in preeclamptic placentas, using various platforms and techniques. [7][8][9][10][11][12][13][14]21,23 Among these studies, there have been some conflicting results.…”

“…[7][8][9][10][11][12]21,22 Meanwhile, for the first time to our knowledge, several miRNAs (miR-17, miR-17-3p, miR-19b1, miR-92a1, miR-379, miR-524, miR-151, miR-218) were found to be aberrantly expressed in sPE placentas.…”

The effect of sulodexide on placental mitochondria function in rats with experimental preeclampsia

“…Несмотря на то, что патогенез и этиология ПЭ окончательно не выяснены; во многих исследованиях показано, что дисфункция митохондрий плаценты является первым звеном патофизиологического каскада, приводящего к развитию осложнения [3][4][5][6]. Выявлена высокая частота ПЭ у женщин с наследственными митохондриальными болезнями, обнаружено повышение общего количества плацентарных митохондрий у рожениц с ПЭ [7], а также дегенеративные изменения их морфологии и нарушение функций [4].…”

“…Снижение этого показателя указывает на дисфункцию митохондрий и прежде всего на нарушение окислительного фосфорилирования [18]. Таким образом, снижение ДК в митохондриях, выделенных из плацент крыс с ЭП, полученное в наших экспериментах, согласуется с современными представлениями о патогенезе ПЭ [3,4,6] и свидетельствует о разобщении дыхания и окислительного фосфорилирования. Опасность разобщения заключается в повышении образования активных форм кислорода (в результате утечки электронов) и в снижении синтеза АТР.…”