Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis

Kuei-Pin Chung, Chia-Lang Hsu, Li-Chao Fan, Ziling Huang, Divya Bhatia, Yi-Jung Chen, Shu Hisata, Soo Jung Cho, Kiichi Nakahira, Mitsuru Imamura, Mary E. Choi, Chong-Jen Yu, Suzanne M. Cloonan and Augustine M. K. Choi ()
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Kuei-Pin Chung: Weill Cornell Medicine
Chia-Lang Hsu: National Taiwan University Hospital
Li-Chao Fan: Weill Cornell Medicine
Ziling Huang: Weill Cornell Medicine
Divya Bhatia: Weill Cornell Medicine
Yi-Jung Chen: National Taiwan University Hospital
Shu Hisata: Weill Cornell Medicine
Soo Jung Cho: Weill Cornell Medicine
Kiichi Nakahira: Weill Cornell Medicine
Mitsuru Imamura: Weill Cornell Medicine
Mary E. Choi: Weill Cornell Medicine
Chong-Jen Yu: Weill Cornell Medicine
Suzanne M. Cloonan: Weill Cornell Medicine
Augustine M. K. Choi: Weill Cornell Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11327-1

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