Increased placental mitochondrial fusion in gestational diabetes mellitus: an adaptive mechanism to optimize feto-placental metabolic homeostasis?

Abstract

IntroductionGestational diabetes mellitus (GDM), a common pregnancy disorder, increases the risk of fetal overgrowth and later metabolic morbidity in the offspring. The placenta likely mediates these sequelae, but the exact mechanisms remain elusive. Mitochondrial dynamics refers to the joining and division of these organelles, in attempts to maintain cellular homeostasis in stress conditions or alterations in oxygen and fuel availability. These remodeling processes are critical to optimize mitochondrial function, and their disturbances characterize diabetes and obesity.Methods and resultsHerein we show that placental mitochondrial dynamics are tilted toward fusion in GDM, as evidenced by transmission electron microscopy and changes in the expression of key mechanochemical enzymes such as OPA1 and active phosphorylated DRP1. In vitro experiments using choriocarcinoma JEG-3 cells demonstrated that increased exposure to insulin, which typifies GDM, promotes mitochondrial fusion. As placental ceramide induces mitochondrial fission in pre-eclampsia, we also examined ceramide content in GDM and control placentae and observed a reduction in placental ceramide enrichment in GDM, likely due to an insulin-dependent increase in ceramide-degrading ASAH1 expression.ConclusionsPlacental mitochondrial fusion is enhanced in GDM, possibly as a compensatory response to maternal and fetal metabolic derangements. Alterations in placental insulin exposure and sphingolipid metabolism are among potential contributing factors. Overall, our results suggest that GDM has profound impacts on placental mitochondrial dynamics and metabolism, with plausible implications for the short-term and long-term health of the offspring.

Placental and maternal sFlt1/PlGF expression in gestational diabetes mellitus

“…Fetal hyperglycemia, hyperinsulinemia, hypoxia as well as placental mitochondrial fusion that promote placental 'anabolism' are associated with placental hypervascularisation in GDM compared to normal pregnancies 7,50,51 . In accordance with an environment that promotes vascularization, in GDM placentae we described no differences in placental sFlt1 expression while we reported a significant increase of pro-angiogenic PlGF relative to CTRL.…”

“…Abbade et al confirmed the placenta protective role from the harmful effects of GDM. They reported in GDM pregnancies that a reduced placental ceramide facilitate anabolism in the fetalplacental unit by upregulating the acid ceramidase ASAH1, an enzyme involved in the degradation of ceramide into sphingosine and fatty acids, thus avoiding the enhanced mitochondrial fission and cell death typical of PE 7 .…”

“…GDM, if not adequately recognized and treated, is associated with high maternal and fetal morbidity, recurring as Type II diabetes months or years after pregnancy. The placenta is exposed as well to hyperglycemia during GDM but it mounts adaptive responses such as enhancing placental mitochondrial fusion to compensate hyperglycemia-induced mitochondrial damage as well as to support physiological fetal development 6,7 . Overall, GDM placentae are in a pro-angiogenic state, presenting more endothelial cells and placental blood vessels per chorionic villi 8 .…”

Macronutrient intake during pregnancy in women with a history of obesity or gestational diabetes and offspring adiposity at 5 years of age

“…Similar data on the first half of pregnancy is lacking and the flux of lipids to the fetus is considerably lower at <20 weeks gestation than at term [28]. However, GDM is characterized by various maternal metabolic abnormalities (e.g., elevated glucose and insulin) already in early pregnancy [33,34], and early changes in placental metabolism and growth in response to disturbed maternal metabolism are increasingly recognized as potential factors in the pathogenesis of fetal adiposity [35][36][37][38]. Considering our observation of increased offspring adiposity in women with GDM with high first half of pregnancy n-3 PUFA intake, it is possible that placental n-3 PUFA metabolism is altered in GDM already in the first half of pregnancy.…”

The association of serum ferritin levels in predicting the outcome in GDM pregnancies

“…The cause of concern with gestational diabetes mellitus is that; the onset of gestational diabetes mellitus coincides with the period of maximum growth of the fetus during the period of gestation. One of the important mechanisms that is used to explain the development of gestational diabetes mellitus is that of oxidative stress and systemic inflammation associated with obesity [6,7] . One among the factors responsible for generation of free radicals and cause inflammation is found to be the presence of abnormally high amount of elemental iron [8,9] .…”