Mitofusins Regulate Lipid Metabolism to Mediate the Development of Lung Fibrosis
Description
Mitochondria form a dynamic intracellular network through fusion and fission to regulate cellular metabolism. Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In this study, 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 surfactant lipid metabolism, where loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase (FASN) deficiency exacerbates bleomycin-induced lung fibrosis. We demonstrate that AEC2 cell lipid metabolism confers a protective and adaptive response against lung fibrosis and propose a novel tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung.