Abstract
Fetal growth is critically dependent on energy metabolism in the placenta, which drives active exchange of nutrients. Placental oxygen levels are therefore vital, and chronic hypoxia during pregnancy impairs fetal growth. Here we tested the hypothesis that placental hypoxia alters mitochondrial electron transport chain (ETS) function, and sought to identify underlying mechanisms. We cultured human placental cells under different oxygen concentrations. Mitochondrial respiration was measured, alongside levels of ETS complexes. Additionally, we studied placentas from sea-level and high-altitude pregnancies. After 4 d at 1% O2 (1.01 KPa), complex I-supported respiration was 57% and 37% lower, in trophoblast-like JEG3 cells and fibroblasts, respectively, compared with controls cultured at 21% O2 (21.24 KPa); complex IV-supported respiration was 22% and 30% lower. Correspondingly, complex I levels were 45% lower in placentas from high-altitude pregnancies than those from sea-level pregnancies. Expression of HIF-responsive microRNA-210 was increased in hypoxic fibroblasts and high-altitude placentas, whilst expression of its targets, iron-sulfur cluster scaffold (ISCU) and cytochrome c oxidase assembly protein (COX10), decreased. Moreover, protein synthesis inhibition, a feature of the high-altitude placenta, also suppressed ETS complex protein levels. Our results demonstrate that mitochondrial function is altered in hypoxic human placentas, with specific suppression of complexes I and IV compromising energy metabolism and potentially contributing to impaired fetal growth.
Highlights
During the first trimester of pregnancy, the human fetus develops in an environment characterised by a very low partial pressure of oxygen [1], which is strikingly close to that experienced by mountaineers high on Mt Everest [2]
To investigate whether mitochondrial function was altered in hypoxic placental cells, we first compared respiration in primary human placental fibroblasts cultured under 21% O2 and hypoxic (1% O2) conditions
Complex I-supported state 3 rates were 43% and 36% lower in fibroblasts cultured at 1% O2 compared with those cultured at 10% O2 (p,0.05) and 21% O2, respectively (Figure 1A), and there was no significant difference in respiratory control ratios (RCRs; state 3/state 2) between difference culture conditions, suggesting no alteration in proton leak
Summary
During the first trimester of pregnancy, the human fetus develops in an environment characterised by a very low partial pressure of oxygen (pO2) [1], which is strikingly close to that experienced by mountaineers high on Mt Everest [2]. It has been proposed that the high altitude placenta undergoes metabolic remodelling to lower its own oxygen consumption, thereby maintaining oxygen delivery to the fetus but at the cost of altered substrate delivery. This concept has been extensively reviewed by ourselves and others [8,9], yet the underlying mechanisms remain unresolved
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