@article{02803598ae804563b21bab30ca38fec0,
title = "Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis",
abstract = "Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. However, the role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. Here we report that the absence of the mitochondrial fusion proteins mitofusin1 (MFN1) and mitofusin2 (MFN2) in murine AEC2 cells leads to morbidity and mortality associated with spontaneous lung fibrosis. We uncover a crucial role for MFN1 and MFN2 in the production of surfactant lipids with MFN1 and MFN2 regulating the synthesis of phospholipids and cholesterol in AEC2 cells. Loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase deficiency in AEC2 cells exacerbates bleomycin-induced lung fibrosis. We propose a tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung.",
author = "Chung, {Kuei Pin} and Hsu, {Chia Lang} and Fan, {Li Chao} and Ziling Huang and Divya Bhatia and Chen, {Yi Jung} and Shu Hisata and Cho, {Soo Jung} and Kiichi Nakahira and Mitsuru Imamura and Choi, {Mary E.} and Yu, {Chong Jen} and Cloonan, {Suzanne M.} and Choi, {Augustine M.K.}",
note = "Funding Information: The authors thank Dr. Brigid L. M. Hogan in Duke University for sharing the SftpcCreERT2+/+ mice, Dr. Clay F. Semenkovich in Washington University in St. Louis for sharing the FasnloxP/loxP mice, and Dr. Bi-Sen Ding in Weill Cornell Medicine (WCM) for sharing the Rosa26tdTomato+/+ mice. The authors thank Maria Plataki and Kristen Schiffer (WCM) for animal husbandry, and also thank the WCM Microscopy and Image Analysis Core Facility, Flow Cytometry Core Facility, Genomic Resources Core Facility, and the support by the Translational Research Program at Pathology and Laboratory Medicine for assistance in this study. The authors thank the Lipidomics Core, funded by K01-AG045335 and R01 AG056387–01, of Columbia University for lipidomic analysis. The authors thank the Microscopy Core Facility in Department of Medical Research, National Taiwan University Hospital (NTUH), for helping the revision. This work was supported by National Institutes of Health grants P01 HL114501 (A.M.K.C.), R01 HL132198 and R01 HL133801 (A.M.K.C. and M.E.C.), R00 HL125899 (S.M.C), KL2-TR-002385 (K.N.), K08 HL138285 (S.J.C.), American Lung Association Award RG-512060 (S.J.C.), and NTUH grant NTUH.108-N03 (K.P.C.). The TEM was acquired with funds from NIH Shared Instrumentation Grant (S10RR027699) for shared resources, and the flow cytometric cell soring was supported by the Office of the Director of NIH under Award Number S10OD019986 to the Hospital for Special Surgery. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-11327-1",
language = "English (US)",
volume = "10",
journal = "Nat Commun",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}