Mitochondrial dysfunction and impaired DNA damage repair through PICT1 dysregulation in alveolar type II cells in emphysema.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2024-11-22 DOI:10.1186/s12964-024-01896-0

Hannah Simborio, Hassan Hayek, Beata Kosmider, John W Elrod, Sudhir Bolla, Nathaniel Marchetti, Gerard J Criner, Karim Bahmed

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引用次数: 0

Abstract

Background: Alveolar type II (ATII) cells have a stem cell potential in the adult lung and repair the epithelium after injury induced by harmful factors. Their damage contributes to emphysema development, characterized by alveolar wall destruction. Cigarette smoke is the main risk factor for this disease development.

Methods: ATII cells were obtained from control non-smoker and smoker organ donors and emphysema patients. Isolated cells were used to study the role of PICT1 in this disease. Also, a cigarette smoke-induced murine model of emphysema was applied to define its function in disease progression further.

Results: Decreased PICT1 expression was observed in human and murine ATII cells in emphysema. PICT1 was immunoprecipitated, followed by mass spectrometry analysis. We identified MRE11, which is involved in DNA damage repair, as its novel interactor. PICT1 and MRE11 protein levels were decreased in ATII cells in this disease. Moreover, cells with PICT1 deletion were exposed to cigarette smoke extract. This treatment induced cellular and mitochondrial ROS, cell cycle arrest, nuclear and mitochondrial DNA damage, decreased mitochondrial respiration, and impaired DNA damage repair.

Conclusions: This study indicates that PICT1 dysfunction can negatively affect genome stability and mitochondrial activity in ATII cells, contributing to emphysema development. Targeting PICT1 can lead to novel therapeutic approaches for this disease.

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肺气肿患者肺泡 II 型细胞的线粒体功能障碍和通过 PICT1 失调导致的 DNA 损伤修复受损。

背景：肺泡 II 型（ATII）细胞在成人肺中具有干细胞潜能，可在有害因素诱发损伤后修复上皮细胞。它们的损伤会导致肺气肿的发生，其特征是肺泡壁的破坏。吸烟是导致肺气肿的主要危险因素：方法：从对照组非吸烟者、吸烟者器官捐献者和肺气肿患者身上获取 ATII 细胞。方法：从对照组非吸烟者、吸烟者器官捐献者和肺气肿患者身上获得 ATII 细胞，用分离的细胞研究 PICT1 在这种疾病中的作用。此外，还应用了香烟烟雾诱导的小鼠肺气肿模型，以进一步确定其在疾病进展中的功能：结果：在肺气肿患者的人和小鼠 ATII 细胞中观察到 PICT1 表达减少。对 PICT1 进行免疫沉淀，然后进行质谱分析。我们发现参与 DNA 损伤修复的 MRE11 是其新的互作因子。在这种疾病的 ATII 细胞中，PICT1 和 MRE11 蛋白水平下降。此外，PICT1缺失的细胞暴露于香烟烟雾提取物中。这种处理会诱发细胞和线粒体 ROS、细胞周期停滞、核和线粒体 DNA 损伤、线粒体呼吸减少以及 DNA 损伤修复受损：这项研究表明，PICT1 功能障碍会对 ATII 细胞的基因组稳定性和线粒体活性产生负面影响，从而导致肺气肿的发生。以 PICT1 为靶点可为这种疾病带来新的治疗方法。

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

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.