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.
Highlights
Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis
Examination of genes included in the mitochondrial organization annotation revealed the upregulation of genes involved in mitochondrial dynamic regulation mitochondrial apoptotic control, and mitochondrial oxidative phosphorylation (Fig. 1c, d and Supplementary Data 1), while there was downregulation of genes involved in mitophagy (Pink[1], Bnip[3], and Atg13) (Fig. 1e)
Considering Mfn1/2iΔAEC2 mice develop spontaneous lung fibrosis, we evaluated whether the transcriptomic response in Mfn1/2−/− AEC2 cells at baseline resembled those in the Mfn1−/− or Mfn2−/− AEC2 cells after bleomycin treatment, and whether Mfn1/2−/− AEC2 cells had functional annotations in common with control AEC2 cells after bleomycin treatment
Summary
Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. The role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. 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. 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. AEC2 cells primarily function to secrete lung surfactant, a surface-active lipoprotein complex containing ~90%. Little is known about the functional role of mitochondrial-dependent lipid metabolism in surfactant producing AEC2 cells. Mitochondria form an interconnected intracellular network, altering size and shape via processes of fission and fusion which are tightly regulated to meet cellular metabolic demands[9,10]
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