胎盘线粒体钙单转运体调节后代对代谢功能障碍的易感性

IF 6.6 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Seokwon Jo , Grace Chung , Yu-Jin Youn , Charlotte Hunt , Ava Hill , Megan Beetch , Brian Akhaphong , Elizabeth A. Morgan , Perrie F. O'Tierney-Ginn , Sarah A. Wernimont , Emilyn U. Alejandro
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引用次数: 0

摘要

线粒体对调节代谢至关重要,但它们在胎盘中的作用以及它们如何影响后代的代谢和长期健康尚不清楚,尽管它们通常与妊娠并发症有关。为了研究这一点,我们使用了一个胎盘特异性缺失线粒体钙单转运蛋白(Pl-MCUKO)的遗传模型,并评估了成年后代的代谢轨迹。我们发现,在基线上,野生型动物的雌性胎盘滋养细胞比雄性表现出更高的呼吸速率。MCU缺失会损害雌性胎盘的线粒体功能,并伴有蛋白质和脂质代谢代谢谱的明显变化。转录组分析显示胎盘细胞生长途径减少,这与pl - mccuko中胎盘变小和胚胎体重减轻的情况一致。虽然在子宫内MCU缺失会影响胎儿生长,但它不足以引起出生后体重的永久性变化,因为这些缺陷在成年后正常化,在pl - mccuko后代中葡萄糖稳态正常。然而,与对照组相比,当接受高脂肪饮食挑战时,pl - mccuko雌性小鼠表现出体重增加减少,葡萄糖和胰岛素耐受性改善,脂肪库减少,运动活动增加。这种改善的代谢谱与胰腺β细胞质量减少有关,但保留了β细胞功能。这些发现为胎盘线粒体功能通过调节关键代谢组织影响雌性后代的长期代谢健康提供了直接证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Placental mitochondrial calcium uniporter modulates offspring susceptibility to metabolic dysfunction
Mitochondria are crucial for regulating metabolism, but their role in the placenta and how they may shape offspring metabolism and long-term health remains unclear, despite being commonly associated with pregnancy complications. To investigate this, we used a genetic model with placenta-specific deletion of the mitochondrial calcium uniporter (Pl-MCUKO) and assessed the metabolic trajectory of adult offspring. We found that, at baseline, female placental trophoblasts in wild-type animals exhibited higher respiration rates than males. MCU deletion impaired mitochondrial function specifically in female placentas and was accompanied by distinct changes in the metabolomic profiles of protein and lipid metabolism. Transcriptome analysis revealed reduced placental cellular growth pathways, consistent with smaller placentas and reduced embryonic body weights in Pl-MCUKO. Although in utero MCU deletion affected fetal growth, it was insufficient to cause permanent postnatal changes in body weight, as these deficits normalized in adulthood, with normal glucose homeostasis in Pl-MCUKO offspring. However, when challenged with a high-fat diet, Pl-MCUKO females exhibited reduced weight gain, improved glucose and insulin tolerance, smaller fat depots, and increased ambulatory activity compared to controls. This improved metabolic profile was associated with reduced pancreatic β-cell mass but preserved β-cell function. These findings provide direct evidence that placental mitochondrial function can influence the long-term metabolic health of female offspring by modulating key metabolic tissues.
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来源期刊
Molecular Metabolism
Molecular Metabolism ENDOCRINOLOGY & METABOLISM-
CiteScore
14.50
自引率
2.50%
发文量
219
审稿时长
43 days
期刊介绍: Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.
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