Mitochondrial fission and bioenergetics mediate human lung fibroblast durotaxis
Ting Guo, … , Hong Peng, Yong Zhou
Ting Guo, … , Hong Peng, Yong Zhou
Published November 24, 2022
Citation Information: JCI Insight. 2023;8(1):e157348. https://doi.org/10.1172/jci.insight.157348.
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Research Article Cell biology Pulmonology

Mitochondrial fission and bioenergetics mediate human lung fibroblast durotaxis

Abstract

Pulmonary fibrosis is characterized by stiffening of the extracellular matrix. Fibroblasts migrate in the direction of greater stiffness, a phenomenon termed durotaxis. The mechanically guided fibroblast migration could be a crucial step in the progression of lung fibrosis. In this study, we found primary human lung fibroblasts sense increasing matrix stiffness with a change of mitochondrial dynamics in favor of mitochondrial fission and increased production of ATP. Mitochondria polarize in the direction of a physiologically relevant stiffness gradient, with conspicuous localization to the leading edge, primarily lamellipodia and filopodia, of migrating lung fibroblasts. Matrix stiffness–regulated mitochondrial fission and durotactic lung fibroblast migration are mediated by a dynamin-related protein 1/mitochondrial fission factor–dependent (DRP1/MFF-dependent) pathway. Importantly, we found that the DRP1/MFF pathway is activated in fibrotic lung myofibroblasts in both human IPF and bleomycin-induced mouse lung fibrosis. These findings suggest that energy-producing mitochondria need to be sectioned via fission and repositioned in durotactic lung fibroblasts to meet the higher energy demand. This represents a potentially new mechanism through which mitochondria may contribute to the progression of fibrotic lung diseases. Inhibition of durotactic migration of lung fibroblasts may play an important role in preventing the progression of human idiopathic pulmonary fibrosis.

Authors

Ting Guo, Chun-sun Jiang, Shan-Zhong Yang, Yi Zhu, Chao He, A. Brent Carter, Veena B. Antony, Hong Peng, Yong Zhou

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Figure 5

Expression of DRP1 and MFF is elevated in lung myofibroblasts in both human IPF and bleomycin injury–induced experimental lung fibrosis in mice.

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Expression of DRP1 and MFF is elevated in lung myofibroblasts in both hu...
(A) C57BL/6 mice were administered 2 U/kg bleomycin (Bleo) or an equal volume of saline (Sal). Lung tissues were harvested at 21 days. Collagen deposition in mouse lungs was evaluated by Masson’s trichrome stain and hydroxyproline content assays. Scale bar = 500 μm. (B and C) Expression of Drp1 (B) and Mff (C) in normal fibroblasts (marked by Npnt expression) and fibroblasts (marked by α-Sma expression) in saline- and bleomycin-treated mouse lungs was evaluated by confocal immunofluorescence microscopy. Fluorescence intensities are mean ± SD of randomly selected areas from 5 mice under each condition. Colocalization of Drp1/Mff expression with (myo)fibroblasts was evaluated by Pearson’s correlation coefficient analyses. Scale bar = 20 μm. (D) Protein levels of Col1a1, α-Sma, Drp1, Mff, and Opa1 in saline-treated and bleomycin-treated mouse lungs were determined by immunoblot. GAPDH was used as loading control. Relative density was normalized to GAPDH. Bar graphs represent mean ± SD from 5 mice in each group. (E and F) Expression of DRP1 (E) and MFF (F) in normal fibroblasts and myofibroblasts in human IPF and normal control lungs was evaluated by confocal immunofluorescence microscopy. Nuclei were stained with DAPI (blue). Fluorescence intensities are mean ± SD of randomly selected areas from 5 mice under each condition. Colocalization of DRP1/MFF expression with (myo)fibroblasts was evaluated by Pearson’s correlation coefficient analyses. Scale bar = 20 μm; a 2-tailed Student’s t test was used for comparison between groups.