Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143.
Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143.
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DOI：
10.1042/cs20160076
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发表时间：
2016-06-01
期刊：
影响因子：
--
通讯作者：
Myatt L
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文献类型：
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作者：
Muralimanoharan S;Maloyan A;Myatt L
妊娠期糖尿病(GDM)高血糖状态的一个易感因素是肥胖。我们之前的研究表明，母亲肥胖的增加与胎盘线粒体呼吸的显著减少有关。此前已有研究表明，microRNA(MiR)-143可调节肿瘤组织从氧化磷酸化到有氧糖酵解的代谢转换。我们推测，妊娠期糖尿病患者胎盘中miR-143表达的变化导致线粒体呼吸减少，有氧糖酵解上调。胎盘组织来自A1GDM(饮食控制)、A2GDM(药物控制)和体重指数(BMI)匹配的对照组(CTRL)。RT-PCR法检测MIR-143的表达。用免疫印迹法检测线粒体复合体、转录因子过氧化物酶体增殖物激活受体γ共激活物1α(Pgc1α)和过氧化物酶体增殖物激活受体γ(PPARγ)、哺乳动物雷帕霉素靶标信号转导成分GLUT1和糖酵解酶[己糖激酶-2(HK-2)、磷酸果糖激酶(Pfk)和乳酸脱氢酶]的表达。用XF24型分析仪测定滋养层呼吸。与A1GDM和CTRL相比，A2GDM胎盘组织中miR-143、线粒体复合体及其下游的PPARγ和Pgc1α的表达显著降低(P<0.01)。A2GDM组胎盘组织HPL水平、糖酵解酶表达、GLUT1和mTOR信号转导水平也显著高于A1GDM组和CTRL组(P<；0.05)。从A2GDM胎盘分离的滋养层细胞线粒体呼吸减少50%。与A2GDM相比，miR-143过表达可增加线粒体呼吸，增加线粒体复合体蛋白表达，降低糖酵解酶表达40%。MiR-143的下调介导了A2GDM患者胎盘从氧化磷酸化到有氧糖酵解的代谢转换。
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.