Idiopathic Pulmonary Fibrosis: Aging, Mitochondrial Dysfunction, and Cellular Bioenergetics

Abstract

At present, the etiology of idiopathic pulmonary fibrosis (IPF) remains elusive. Over the past two decades, however, researchers have identified and described the underlying processes that result in metabolic dysregulation, metabolic reprogramming, and mitochondrial dysfunction observed in the cells of IPF lungs. Metabolic changes and mitochondrial dysfunction in IPF include decreased efficiency of electron transport chain function with increasing production of reactive oxygen species, decreased mitochondrial biogenesis, and impaired mitochondrial macroautophagy, a key pathway for the removal of dysfunctional mitochondria. Metabolic changes in IPF have potential impact on lung cell function, differentiation, and activation of fibrotic responses. These alterations result in activation of TGF-β and predispose to the development of pulmonary fibrosis. IPF is a disease of the aged, and many of these same bioenergetic changes are present to a lesser extent with normal aging, raising the possibility that these anticipated alterations in metabolic processes play important roles in creating susceptibility to the development of IPF. This review explores what is known regarding the cellular metabolic and mitochondrial changes that are found in IPF, and examines this body of literature to identify future research direction and potential points of intervention in the pathogenesis of IPF.

Keywords: aging; bioenergetics; lung fibrosis; mitochondrial dysfunction; mitophagy; senescence.

Figure 1

Schematic of profibrotic pathways mediated by mitochondrial dysfunction. Reduced PGC1α in fibrotic lungs has been associated with insufficient biogenesis and diminished autophagy. Similarly, decreased PINK1, a key modulator of mitophagy, and decreased SIRT3 have been found in AECII from fibrotic lungs associated with mitochondrial dysfunction, and increased activation of TGF-β. Profibrotic macrophages exhibit increased rates of mitophagy and resistance to apoptosis resulting in greater release of TGF-β. TGF-β affects mitochondrial function in fibroblasts through decreasing PINK1, Parkin, and SIRT3. Idiopathic pulmonary fibrosis fibroblasts have increased mtDNA damage, mitochondrial dysfunction, impaired mitochondrial biogenesis, and increased rate of senescence. All of these factors contribute to in fibroblast-to-myofibroblast differentiation. Abbreviations: Ac, acetyl group; ETC, type II alveolar epithelial cell electron transport chain, Mn-SOD, manganese super oxide dismutase; mtDNA, mitochondrial DNA, mtROS, mitochondrial reactive oxygen species; NOX4, NADPH oxidase 4; Nrf2, nuclear factor (erythroid-derived 2)-like-2 factor; OGG1, 8-oxoguanine DNA glycosylase 1; PDGFR, platelet-derived growth factor receptor; PINK1, PTEN-induced putative kinase 1; UCP2, uncoupling protein 2; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha.

Figure 2

Schematic of metabolic dysfunction in lung fibrosis. Idiopathic pulmonary fibrosis (IPF) lung have a generalized decrease in late stages of glycolysis compared with normal lungs; however, increased levels of lactate were found in IPF lungs suggesting that all products of glycolysis are shuttled toward lactate production. Several studies have been focused in metabolic alterations of specific cell compartments in the IPF lung. IPF lung fibroblasts show decreased glycolytic function determined by extracellular acid production. IPF myofibroblasts have been reported to have higher expression of glycolytic enzymes and lactate content. Single cell RNA sequence data in alveolar epithelial cells show low expression of enzymes necessary for lipid metabolism. By contrast, alveolar macrophages isolated from bleomycin-treated mice show glycolytic reprogramming and increase fatty acid oxidation. Abbreviations: AECII, type II alveolar epithelial cell; GluT1, glucose transporter 1; HK2, hexokinase 2; LDH5, lactate dehydrogenase 5; LDHB, lactate dehydrogenase B; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3.