Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic age-related lung disease with high mortality that is characterized by abnormal scarring of the lung parenchyma. There has been a recent attempt to define the age-associated changes predisposing individuals to develop IPF. Age-related perturbations that are increasingly found in epithelial cells and fibroblasts from IPF lungs compared with age-matched cells from normal lungs include defective autophagy, telomere attrition, altered proteostasis, and cell senescence. These divergent processes seem to converge in mitochondrial dysfunction and metabolic distress, which potentiate maladaptation to stress and susceptibility to age-related diseases such as IPF. Therapeutic approaches that target aging processes may be beneficial for halting the progression of disease and improving quality of life in IPF patients.

Figure 1. Mitochondrial dysfunction and lung fibrosis.

Aging and ER stress cause mitochondrial dysfunction in type II alveolar epithelial cells (AECIIs) by diminishing the expression of the mitochondrial homeostasis regulator PINK1. Deficiency of PINK1 causes mitochondrial dysfunction, which is characterized by low activity of the electron transport chain (ETC) complexes I and IV, alterations in mtDNA metabolism, and insufficient mitophagy, leading to increased susceptibility to apoptosis and induction of TGF-β. TGF-β stimulation of lung fibroblasts has been shown to decrease PINK1 levels and promote insufficient mitophagy and myofibroblast differentiation. Additionally, aging and TGF-β stimulation reduce the expression of SIRT3. SIRT3 deficiency increases levels of acetylated (Ac) MnSOD and consequently increases mitochondrial ROS levels and mtDNA damage, which are also related to low expression of the DNA repair enzyme 8-oxoguanine-DNA glycosylase-1 (OGG1).

Figure 2. Mechanisms of aging and the pathogenesis of IPF.

Several of the aging cell perturbations associated with IPF lungs converge to produce mitochondrial dysfunction, including DNA damage/genomic instability, altered proteostasis, reduced autophagy, and telomere attrition. Additionally, mitochondrial dysfunction can lead to cellular senescence and stem cell exhaustion. We propose that mitochondrial dysfunction plays a central role in the process of aging and the pathogenesis of IPF.