The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis

Table 1

Summary of interactions between the ECM and mitochondria in pulmonary fibrosis in vivo and in vitro studies.

Interaction with mitochondria via	In vivo studies	In vitro studies	Ref.
Mechanical tensions	(i) The lung tissue biomechanic alteration influencing cells via intracellular organelle dysfunction includes mitochondria	(i) Mechanical stress influences on mitochondria structure and function, reduces mitochondrial membrane potential and ATP production, and induces ROS production, alter fusion, and fission	[18, 37–39, 63]
Cytoskeleton		(i) Cytoskeletal toxins induce shortening of mitochondria	[46]
Integrins	(i) αVβ6-mediated activation of TGF-β is necessary for the development of fibrosis in lung-disease models	(i) Integrin ligands stimulate mitochondrial function	[50, 51, 53, 80]
Signaling	(i) Low PTEN levels induce fibrogenesis	(i) FAK and STAT3 inhibition abolished mitochondrial function	[52–54, 81]
ROS	(i) Mitochondrial ROS in AEC mediate mtDNA damage and fibrosis; (ii) Mitochondrial ROS are essential to the development of pulmonary fibrosis; (iii) Antioxidant treatment attenuates the bleomycin-induced oxidative burden and subsequent pulmonary fibrosis; (iv) The absence of extracellular superoxide dismutase exacerbates conditions that lead to inflammation and pulmonary fibrosis	(i) mtDNA leads to ROS production, inflammation, and I consequence fibrosis; (ii) TGF-β1 induces prolonged mitochondrial ROS generation	[73, 82–85]
Apoptosis	(i) Low PTEN levels inhibit mitochondrial-dependent apoptosis	(i) The proapoptotic proteins contribute to stretch-induced mitochondrial apoptosis	[52, 65, 81]
Calcium	(i) The S100 calcium-binding protein A4 level is elevated in the lungs of patients with IPF	(i) Calcium influx into the mitochondria impairs mitochondrial function; (ii) Calcium-sensitive receptors are upregulated in activated lung fibroblasts and reduce markers implicated in pulmonary fibrosis	[46, 69, 86]
Cytokines	(i) TGF-β induces ECM and ROS overproduction, decreases mitochondrial membrane potential, and inhibits mitophagy	(i) Mitochondria dysfunction increase cytokines production in lung epithelium	[73, 87, 88]