The Role of Placental MFF-Mediated Mitochondrial Fission in Gestational Diabetes Mellitus.

IF 2.8 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM
Lijie Wei, Chenyun Fang, Yi Jiang, Huiting Zhang, Peng Gao, Xuan Zhou, Shenglan Zhu, Yuanyuan Du, Rui Su, Lili Guo, Mengzhou He, Shaoshuai Wang, Ling Feng, Jun Yu
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引用次数: 0

Abstract

Introduction: Gestational diabetes mellitus (GDM) refers to hyperglycemia first recognized during pregnancy, characterized by decreased insulin sensitivity and impaired glucose metabolism. Dynamic fusion and fission processes within mitochondria play critical roles in maintaining glucose metabolism homeostasis. Given the fundamental role of mitochondrial fission factor (MFF) in mitochondrial fission, the intention of this study was to investigate mitochondrial dynamics in the placentae of GDM patients and explore the role of MFF in the etiopathogenesis and progression of GDM through the modulation of glucose metabolism and insulin resistance.

Methods: 40 Placental tissues were obtained from pregnant women undergoing cesarean section with GDM (n=20) and those with normoglycemia (n=20). To mimic the intrauterine high glucose environment, immortalized human-derived first-trimester extravillous trophoblast cells HTR8/SVneo were used and treated in a high glucose environment. Immunofluorescence was utilized to analyze MFF expression in placental tissues and mitochondrial length in HTR8/SVneo cells. The expression levels of glucose transporters (GLUTs) and other pivotal proteins involved in mitochondrial dynamics and the insulin signaling pathway, were assessed by Western blotting. Additionally, cellular glucose uptake capacity was determined using a glucose assay kit.

Results: MFF expression was greater in the GDM group than in the normoglycemic group. In a high-glucose environment, the expression of fusion-related proteins OPA1, MFN1 and MFN2 decreased while the expression of DRP1 and MFF increased, indicating that the mitochondrial dynamics of trophoblast cells shift toward fission. Elevated mitochondrial fission hinders the insulin signaling pathway, resulting in a reduction in glucose uptake by HTR8/SVneo cells and a concurrent decrease in GLUT4 expression.

Discussion: Our study demonstrates that MFF-mediated mitochondrial fission inhibits insulin sensitivity and upregulates glucose transport in GDM, which is related to offspring exposure to a hyperglycemic intrauterine environment. These results provide a novel therapeutic target for addressing GDM that may mitigate unfavorable pregnancy outcomes.

胎盘mff介导的线粒体分裂在妊娠期糖尿病中的作用。
简介:妊娠期糖尿病(Gestational diabetes, GDM)是指妊娠期间首次发现的高血糖,以胰岛素敏感性降低、糖代谢受损为特征。线粒体内的动态融合和裂变过程在维持葡萄糖代谢稳态中起着关键作用。鉴于线粒体裂变因子(mitochondrial fission factor, MFF)在线粒体分裂中的基础性作用,本研究旨在研究GDM患者胎盘的线粒体动力学,并通过调节葡萄糖代谢和胰岛素抵抗来探讨MFF在GDM发病和进展中的作用。方法:取剖宫产合并GDM孕妇(n=20)和血糖正常孕妇(n=20)胎盘组织40份。为了模拟宫内高糖环境,我们在高糖环境中使用了永生化的人源性孕早期上皮外滋养细胞HTR8/SVneo。采用免疫荧光法分析胎盘组织中MFF的表达及HTR8/SVneo细胞线粒体长度。葡萄糖转运蛋白(GLUTs)和其他参与线粒体动力学和胰岛素信号通路的关键蛋白的表达水平通过Western blotting进行评估。此外,使用葡萄糖测定试剂盒测定细胞葡萄糖摄取能力。结果:GDM组MFF表达明显高于血糖正常组。在高糖环境下,融合相关蛋白OPA1、MFN1和MFN2的表达降低,DRP1和MFF的表达升高,表明滋养层细胞线粒体动力学向裂变方向转变。升高的线粒体裂变阻碍了胰岛素信号通路,导致HTR8/SVneo细胞葡萄糖摄取减少,同时GLUT4表达减少。讨论:我们的研究表明,mff介导的线粒体分裂抑制胰岛素敏感性并上调GDM中的葡萄糖转运,这与后代暴露于高血糖的宫内环境有关。这些结果为解决GDM提供了一个新的治疗靶点,可以减轻不良妊娠结局。
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来源期刊
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Pharmacology, Toxicology and Pharmaceutics-Pharmacology
CiteScore
5.90
自引率
6.10%
发文量
431
审稿时长
16 weeks
期刊介绍: An international, peer-reviewed, open access, online journal. The journal is committed to the rapid publication of the latest laboratory and clinical findings in the fields of diabetes, metabolic syndrome and obesity research. Original research, review, case reports, hypothesis formation, expert opinion and commentaries are all considered for publication.
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