Mitochondria dysfunction and metabolic reprogramming as drivers of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. It is characterized by deposition of extracellular matrix proteins, like collagen and fibronectin in the lung interstitium leading to respiratory failure. Our understanding of the pathobiology underlying IPF is still incomplete; however, it is accepted that aging is a major risk factor in the disease while growing evidence suggests that the mitochondria plays an important role in the initiation and progression of pulmonary fibrosis. Mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, fibroblasts, and macrophages) promoting low resilience and increasing susceptibility to activation of profibrotic responses. Here we summarize changes in mitochondrial numbers, biogenesis, turnover and associated metabolic adaptations that promote disrepair and fibrosis in the lung. Finally, we highlight new possible therapeutic approaches focused on ameliorate mitochondrial dysfunction.

Keywords: Aging; Epithelial cells; Fibroblast; Fibrosis; Macrophage; Mitochondrial dysfunction.

Graphical abstract

Fig. 1

Mitochondrial dysfunction in the IPF lung: origins and consequences. The loss of mitochondria homeostasis is a common aspect of the fibrotic lung and can appear at different stages of the mitochondria life cycle. In the IPF lung, the specific features of mitochondrial dysfunction (in red) exhibited are cell-type dependent, triggering an array of diverse metabolic changes and alteration (in blue). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article).

Fig. 2

Metabolic pathways targeted by new antifibrotic drugs. In order to maintain cellular homeostasis and prevent profibrotic events, modulation of glycolysis, fatty acid oxidation and synthesis are key. New potential therapies are in development targeting these main metabolic pathways; with some of them already at different stages in clinical trials. Drugs are highlighted in white boxes, main metabolic pathways in yellow boxes, metabolites in green and transcription factors in pink. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article).