Abstract
Idiopathic pulmonary fibrosis (IPF) is age-related interstitial lung disease of unknown etiology. About 100,000 people in the U.S have IPF, with a 3-year median life expectancy post-diagnosis. The development of an effective treatment for pulmonary fibrosis will require an improved understanding of its molecular pathogenesis and the “normal” and “pathological’ hallmarks of the aging lung. An important characteristic of the aging organism is its lowered capacity to adapt quickly to, and counteract, disturbances. While it is likely that DNA damage, chronic endoplasmic reticulum (ER) stress, and accumulation of heat shock proteins are capable of initiating tissue repair, recent studies point to a pathogenic role for mitochondrial dysfunction in the development of pulmonary fibrosis. These studies suggest that damage to the mitochondria induces fibrotic remodeling through a variety of mechanisms including the activation of apoptotic and inflammatory pathways. Mitochondrial quality control (MQC) has been demonstrated to play an important role in the maintenance of mitochondrial homeostasis. Different factors can induce MQC, including mitochondrial DNA damage, proteostasis dysfunction, and mitochondrial protein translational inhibition. MQC constitutes a complex signaling response that affects mitochondrial biogenesis, mitophagy, fusion/fission and the mitochondrial unfolded protein response (UPRmt) that, together, can produce new mitochondria, degrade the components of the oxidative complex or clearance the entire organelle. In pulmonary fibrosis, defects in mitophagy and mitochondrial biogenesis have been implicated in both cellular apoptosis and senescence during tissue repair. MQC has also been found to have a role in the regulation of other protein activity, inflammatory mediators, latent growth factors, and anti-fibrotic growth factors. In this review, we delineated the role of MQC in the pathogenesis of age-related pulmonary fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) represents one of the most aggressive and irreversible lung diseases, usually diagnosed in the fifth decade of life, carries a very poor prognosis, an unknown etiology and limited therapeutic options [1]
Interaction between mitochondria dysfunction, mTORC complex 1 (mTORC1) and the ubiquitin-proteasome system might represent the key element to understand in depth the mechanism that lead to mitochondrial biogenesis dysregulation in age-related lung fibrosis
[20] as we demonstrated in our study, mitochondria biogenesis is increased in the AECII of old mice through the upregulation of the mTORC1/PGC-1 signaling axis
Summary
Idiopathic pulmonary fibrosis (IPF) represents one of the most aggressive and irreversible lung diseases, usually diagnosed in the fifth decade of life, carries a very poor prognosis, an unknown etiology and limited therapeutic options [1]. Accumulation of unfolded proteins inside the mitochondria leads to activation of the mitochondria unfolded protein response (UPRmt) with the goal of promoting repair, recovery and restore mitochondrial proteostasis Activation of these machineries allows maintenance and regulation of this organelle metabolism, biogenesis, ROS production and mitochondrial DNA (mtDNA) damage repair [4,5]. Disruptions of these processes can subsequently lead to the accumulation of dysfunctional mitochondria, alter the intracellular environment and contribute to the development of age-related lung fibrosis [6]. This review explores the mitochondrial quality control pathways, its association with the development of age-related lung fibrosis and describes new potential therapeutic targets
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