Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143

Abstract

A predisposing factor for development of the hyperglycaemic state of gestational diabetes mellitus (GDM) is obesity. We previously showed that increasing maternal obesity is associated with significant reductions in placental mitochondrial respiration. MicroRNA (miR)-143 has been previously shown to regulate the metabolic switch from oxidative phosphorylation to aerobic glycolysis in cancer tissues. We hypothesized that mitochondrial respiration is reduced and aerobic glycolysis is up-regulated via changes in miR-143 expression in the placenta of women with GDM. Placental tissue was collected at term from women with A1GDM (controlled by diet), A2GDM (controlled by medication) and body mass index (BMI)-matched controls (CTRL). miR-143 expression was measured by RT-PCR. Expression of mitochondrial complexes, transcription factors peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α) and peroxisome proliferator-activated receptor γ (PPARγ), components of mammalian target of rapamycin (mTOR) signalling, glucose transporter GLUT1 and glycolytic enzymes [hexokinase-2 (HK-2), phosphofructokinase (PFK) and lactate dehydrogenase (LDH)] were measured by Western blot. Trophoblast respiration was measured by XF24 Analyser. Expression of miR-143, mitochondrial complexes, and PPARγ and PGC1α, which act downstream of miR-143, were significantly decreased in A2GDM placentae compared with A1GDM and CTRL (P<0.01). Placental hPL (human placental lactogen) levels, expression of glycolytic enzymes, GLUT1 and mTOR signalling were also significantly increased by more than 2-fold in A2GDM compared with A1GDM and CTRL (P<0.05). There was a 50% reduction in mitochondrial respiration in trophoblast cells isolated from A2GDM placentae. Overexpression of miR-143 was able to increase mitochondrial respiration, increase protein expression of mitochondrial complexes and decrease expression of glycolytic enzymes by 40% compared with A2GDM. Down-regulation of miR-143 mediates the metabolic switch from oxidative phosphorylation to aerobic glycolysis in placenta of women with A2GDM.

Review: Placental transport and metabolism of energy substrates in maternal obesity and diabetes

“…These findings were in agreement with a later study in 160 maternal obesity, showing that heightened glucose metabolism in placental explants 161 reduced fatty acid oxidation [19]. In women with pre-existing diabetes [48] or GDM [49], 162 placental activity of mitochondrial electron transport chain complexes was reduced. In 163 GDM, mitochondrial oxygen consumption was reduced, along with increased placental 164 expression of glycolytic enzymes and LDH (marker of aerobic glycolysis) [49].…”

“…In women with pre-existing diabetes [48] or GDM [49], 162 placental activity of mitochondrial electron transport chain complexes was reduced. In 163 GDM, mitochondrial oxygen consumption was reduced, along with increased placental 164 expression of glycolytic enzymes and LDH (marker of aerobic glycolysis) [49]. However, 165 these women had been treated with either insulin or glyburide so effects on placental 166 glucose metabolism cannot be definitively attributed to GDM.…”

Placental endoplasmic reticulum stress and acidosis: relevant aspects in gestational diabetes

“…As a consequence, the studies performed by these authors allow for the identification of not only hyperglycaemia-induced endoplasmic reticulum stress, but also hyperglycaemia-induced acidosis in trophoblast cells, leading to the conclusion that increased lactate concentrations were the cause of the endoplasmic reticulum stress observed in these cells [4]. In agreement with this, in a recent study Muralimanoharan and colleagues found increased lactate dehydrogenase in the placentas of GDM participants, highlighting the relevance of increased anabolic pathway activation, and its relationship with mitochondrial dysfunction, in GDM placentas [14]. Mitochondrial dysfunction is closely related to oxidative stress, which affects GDM placentas [12].…”

Circulating early- and mid-pregnancy microRNAs and risk of gestational diabetes

“…Differences have also been seen in circulating levels of miRNAs (e.g., miR-126, -146a, and -29a) comparing type 2 diabetes (T2D) cases to controls[13, 18-27]. Epigenetic regulatory mechanisms, including miRNAs, may also have important roles in GDM, a condition that shares similar pathophysiologic features to T2D[28-33]. Several small studies have demonstrated differences in placental or umbilical vein endothelial cell miRNA expression at delivery in GDM pregnancies vs. controls[28-33].…”