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

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Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-08-23 , DOI: 10.1016/j.stem.2024.08.001
Le Xu ₁ , Chunting Tan ₁ , Justinn Barr ₁ , Nicole Talaba ₁ , Jamie Verheyden ₁ , Ji Sun Chin ₁ , Samvel Gaboyan ₂ , Nikita Kasaraneni ₂ , Ruth M Elgamal ₁ , Kyle J Gaulton ₁ , Grace Lin ₃ , Kamyar Afshar ₄ , Eugene Golts ₅ , Angela Meier ₆ , Laura E Crotty Alexander ₂ , Zea Borok ₄ , Yufeng Shen ₇ , Wendy K Chung ₈ , David J McCulley ₁ , Xin Sun ₉

Affiliation

Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Surgery, Division of Cardiovascular and Thoracic Surgery, University of California, San Diego, La Jolla, CA, USA.
Department of Anesthesiology, Division of Critical Care, University of California, San Diego, La Jolla, CA, USA.
Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA; JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093, USA.

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.

中文翻译：

线粒体 LONP1 在协调气道祖细胞与后代细胞之间平衡中的环境依赖性作用

虽然所有真核细胞的功能都依赖于线粒体，但在复杂组织中，哪种细胞类型和哪种细胞行为对线粒体缺陷更敏感仍然是不可预测的。在这里，我们表明在小鼠气道中，通过灭活线粒体蛋白酶基因 Lonp1 来损害线粒体功能导致发育过程中祖细胞增殖和分化减少，终末分化纤毛细胞凋亡并在其体内平衡期间被基底祖细胞和杯状细胞取代，以及流感感染后气道祖细胞迁移到受损肺泡失败。ATF4 和综合应激反应（ISR）通路升高并负责气道表型。这种上下文依赖性敏感性是通过 ISR 激活所需的 Bok 的选择性表达来预测的。在伴有鳞状化生的慢性阻塞性肺病（COPD）气道中发现 LONP1 表达降低。这些发现说明了一种细胞能量景观，其中受损的线粒体功能可能有利于病理细胞类型的出现。

更新日期：2024-08-23

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