Nucleolin alleviates endotoxemia-induced myocardial dysfunction via inhibiting Drp1-mediated mitochondrial fission

IF 2.7 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-05-18 DOI:10.1016/j.tice.2025.102964

Ludong Yuan , Yuting Tang , Leijing Yin , Xiaofang Lin , Pengfei Liang , Bimei Jiang

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引用次数: 0

Abstract

Background

Our previous study found that nucleolin expression exerted anti-cardiac injury effects by promoting mitochondrial biogenesis; however, it could not explain the increase in mitochondrial fragmentation during myocardial injury. Mitochondrial fragmentation is associated with mitochondrial fission, but it is unknown whether nucleolin regulates mitochondrial fission. Therefore, this study aims to investigate the mechanism by which nucleolin regulates mitochondrial fission in endotoxemia-induced myocardial dysfunction.

Methods

Nucleolin myocardial-specific knockout mice were used to construct an endotoxemia-induced myocardial dysfunction model. Mitochondrial membrane potential (MMP), ATP production, Mitotracker Red, Transmission Electron Microscope were measured to assess mitochondrial function. Mitochondria were isolated to observe Drp1 translocation to mitochondria. The expression of pGSK-3β-Tyr216, GSK-3β, pDrp1-Ser637, nucleolin and dynamin-related protein 1 (DNM1L, Drp1) were detected using qRT-PCR and western blot.

Results

Following cecum ligation and puncture (CLP) model, cardiac function was impaired, myocardial mitochondrial function declined, mitochondrial morphology became disorganized and fragmented, nucleolin and Drp1 expression was elevated. Myocardial injury and mitochondrial dysfunction were further exacerbated after nucleolin myocardium-specific knockout. Meanwhile, after cellular-level nucleolin interference, it further led to LPS and TNF-α-induced mitochondrial dysfunction and cardiomyocyte damage. Mechanically, nucleolin interference inhibited Drp1 phosphorylation at Ser637 and promoted Drp1 translocation to mitochondria. Myocardial injury caused by nucleolin knockdown was alleviated by the use of P110, an inhibitor of Drp1 mitochondrial translocation.

Conclusion

Endotoxemia-induced myocardial dysfunction is accompanied by increased mitochondrial fragmentation. Nucleolin alleviates endotoxemia-induced myocardial dysfunction by enhancing Drp1 phosphorylation at Ser637, inhibiting Drp1 translocation to the mitochondria and mitochondrial fission.

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核仁蛋白通过抑制drp1介导的线粒体裂变来减轻内毒素血症诱导的心肌功能障碍

前期研究发现，核仁蛋白表达通过促进线粒体生物发生发挥抗心脏损伤作用；然而，这并不能解释心肌损伤时线粒体碎片化的增加。线粒体分裂与线粒体分裂有关，但核蛋白是否调控线粒体分裂尚不清楚。因此，本研究旨在探讨核蛋白在内毒素血症引起的心肌功能障碍中调控线粒体分裂的机制。方法采用核苷心肌特异性敲除小鼠建立内毒素血症诱导心肌功能障碍模型。测定线粒体膜电位（MMP）、ATP生成、Mitotracker Red、透射电镜观察线粒体功能。分离线粒体观察Drp1向线粒体的易位。采用qRT-PCR和western blot检测pGSK-3β-Tyr216、GSK-3β、pDrp1-Ser637、核仁蛋白和动力蛋白相关蛋白1 （DNM1L、Drp1）的表达。结果盲肠结扎穿刺（CLP）模型大鼠心功能受损，心肌线粒体功能下降，线粒体形态紊乱、碎片化，核仁蛋白和Drp1表达升高。核仁蛋白心肌特异性敲除后心肌损伤和线粒体功能障碍进一步加重。同时，细胞水平核蛋白干扰后，进一步导致LPS和TNF-α-诱导的线粒体功能障碍和心肌细胞损伤。从机械上讲，核蛋白干扰抑制了Drp1 Ser637位点的磷酸化，促进了Drp1向线粒体的易位。使用Drp1线粒体易位抑制剂P110可减轻核仁蛋白敲低引起的心肌损伤。结论内毒素血症所致心肌功能障碍伴线粒体断裂增加。核蛋白通过增强Drp1 Ser637位点的磷酸化，抑制Drp1易位到线粒体和线粒体裂变，减轻内毒素血症诱导的心肌功能障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.