Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
Le Xu, Chunting Tan, Justinn Barr, Nicole Talaba, Jamie Verheyden, Ji Sun Chin, Samvel Gaboyan, Nikita Kasaraneni, Ruth M. Elgamal, Kyle J. Gaulton, Grace Lin, Kamyar Afshar, Eugene Golts, Angela Meier, Laura E. Crotty Alexander, Zea Borok, Yufeng Shen, Wendy K. Chung, David J. McCulley, Xin Sun
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Abstract

While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.

Abstract Image

线粒体 LONP1 在协调气道祖细胞与后代细胞之间的平衡中的作用与环境有关
虽然所有真核细胞的功能都依赖于线粒体,但在一个复杂的组织中,哪种细胞类型和哪种细胞行为对线粒体缺乏更敏感仍然无法预测。在这里,我们发现在小鼠气道中,通过使线粒体蛋白酶基因 Lonp1 失活而损害线粒体功能会导致发育过程中祖细胞增殖和分化减少、终末分化的纤毛细胞凋亡并在稳态过程中被基底祖细胞和鹅口疮细胞取代,以及流感感染后气道祖细胞向受损肺泡迁移失败。ATF4 和综合应激反应(ISR)通路升高并导致气道表型。Bok 的选择性表达预测了这种环境依赖性敏感性,而 Bok 是 ISR 激活所必需的。在鳞状化生的慢性阻塞性肺病(COPD)气道中发现 LONP1 表达减少。这些发现说明了线粒体功能受损可能有利于病理细胞类型出现的细胞能量图谱。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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