Alterations in antioxidant system, mitochondrial biogenesis and autophagy in preeclamptic myometrium

Abstract

Preeclampsia is a pregnancy complication which causes significant maternal and fetal morbidity and mortality worldwide. Although intensive research has been performed in the last 40 years, the pathology of preeclampsia is still poorly understood. The present work is a comparative study of the myometrium of women with normal pregnancy, and those with late- and early-onset preeclampsia (n = 10 for each group). We observed significant changes in the levels of antioxidant enzymes, markers of mitochondrial biogenesis and autophagy proteins in preeclamptic myometrium. Levels of superoxide dismutase 1 and catalase were lower in both preeclamptic groups than the control group. In late-onset preeclampsia, expression levels of essential mitochondria-related proteins VDAC1, TFAM, hexokinase 1, PGC-1α and PGC-1β, and autophagy marker LC3A, were significantly elevated. In the myometrium of the early-onset preeclampsia group OPA1 and Bcl-2 were up-regulated compared to those of the control (p < 0.05). These findings suggest that crucial molecular changes in the maternal myometrium occur with the development of preeclampsia.

Platelets in preeclamptic pregnancies fail to exhibit the decrease in mitochondrial oxygen consumption rate seen in normal pregnancies

“…RCR is the ratio of maximal respiration to respiration driven by proton leak and is used to estimate maximal efficiency of energy transduction between the redox potential energy released by the electron transport chain and the formation of the high-energy phosphodiester bond present in ATP. These results are consistent with changes previously found in placental [ 6 , 8–10 , 27 ] and myometrial mitochondria [ 11 ], suggesting that platelets may be useful in the antenatal study of mitochondrial bioenergetics profiles in pregnancies afflicted with preeclampsia or other pregnancy-associated disease. Interestingly, none of the respiratory measurements in platelets harvested from preeclamptic pregnancies was significantly different from that observed in platelets from non-pregnant women, suggesting that the changes observed in preeclampsia may represent failure of a normal, possibly adaptive, biologic mechanism initiated during pregnancy.…”

“…Second, we did not attempt to correlate platelet mitochondrial function with that seen in mitochondria harvested at delivery from placental [ 6–10 ] or myometrial tissues [ 11 ]. A future, more expansive study, harvesting placental or myometrial cells along with platelets from preeclamptic or normal pregnancies, could provide evidence that platelet mitochondria serve as a surrogate for placental or myometrial mitochondria.…”

“…Preeclampsia, a leading cause of maternal and fetal/neonatal morbidity and mortality [ 2–4 ], is characterized by abnormal placentation (imbalance in pro- and anti-angiogenic factors), an inflammatory response with accompanying immunologic dysfunction, placental and maternal systemic endothelial dysfunction, and altered coagulation [ 5 ]. Mitochondria within placental [ 6–10 ] and myometrial [ 11 ] cells harvested at delivery in pregnancies afflicted by preeclampsia demonstrate various histologic (e.g. distorted inner membranes) and functional changes (i.e.…”

Role of Mitochondrial Dysfunction and Reactive Oxygen Species in Mediating Hypertension in the Reduced Uterine Perfusion Pressure Rat Model of Preeclampsia

“…Muralimanoharan et al reported the placental mitochondrial fraction from pre-eclamptic women showed decreased activity of electron transport chain component, complex III with decreased expression of complex I and IV (30). Other studies reported alteration of antioxidant systems (SOD, catalase, GSH/GSSG) in PE placenta (31-34). Another recent study reported that miR-128a causes reduced mitochondrial membrane potential and ATP with increased ROS and caspase activation in HTR-8/SVneo trophoblast cells (35).…”

Placental mitochondria and reactive oxygen species in the physiology and pathophysiology of pregnancy

“…Damaged mitochondria are removed by autophagy ( Figure 3), and in both severe preeclampsia and GDM increased placental autophagy markers have been observed. 34 Placental autophagy markers are altered in association with excessive ROS generation, decreased antioxidant capacity and enhanced mitochondrial turnover, 34 directly linking changes in mitochondrial dynamics to complications of pregnancy.…”