Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis
Journal
Nature Communications
Journal Volume
10
Journal Issue
1
Date Issued
2019
Author(s)
Fan L.-C.
Huang Z.
Bhatia D.
Chen Y.-J.
Hisata S.
Cho S.J.
Nakahira K.
Imamura M.
Choi M.E.
Cloonan S.M.
Choi A.M.K.
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. ? 2019, The Author(s).
SDGs
Other Subjects
bleomycin; fatty acid synthase; mitofusin 1; mitofusin 2; antineoplastic antibiotic; bleomycin; cholesterol; guanosine triphosphatase; Mfn1 protein, mouse; Mfn2 protein, mouse; phospholipid; cell component; disease; inhibition; lipid; metabolism; mitochondrion; morbidity; mortality; protein; surfactant; A-549 cell line; animal cell; animal experiment; animal model; animal tissue; Article; autophagy; cell damage; cell isolation; confocal microscopy; controlled study; DNA fragmentation assay; enzyme deficiency; flow cytometry; gene deletion; gene dosage; gene expression; genotyping technique; glycolysis; histopathology; human; human cell; immunoblotting; immunofluorescence test; immunohistochemistry; lipid fingerprinting; lipid metabolism; lipogenesis; lung fibrosis; lung lavage; mitochondrial dynamics; mitochondrial respiration; MLE-12 cell line; morbidity; mortality; mouse; myofibroblast; nonhuman; oxidative phosphorylation; real time polymerase chain reaction; RNA sequence; transmission electron microscopy; TUNEL assay; animal; biosynthesis; cell culture; drug effect; fibrosing alveolitis; genetics; knockout mouse; lung alveolus epithelium cell; metabolism; pathology; transgenic mouse; Murinae; Alveolar Epithelial Cells; Animals; Antibiotics, Antineoplastic; Bleomycin; Cells, Cultured; Cholesterol; GTP Phosphohydrolases; Idiopathic Pulmonary Fibrosis; Lipid Metabolism; Mice, Knockout; Mice, Transgenic; Mitochondrial Dynamics; Phospholipids
Type
journal article