Abstract
We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-β which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-β mediated profibrotic responses.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable interstitial lung disease of unknown etiology with median survival of only 2 to 3 years from the time of diagnosis [1]
We have previously shown that IPF lung epithelial cells present low levels of PTEN inducible kinase 1 (PINK1) [4], driven by persistent ER stress [23] and chronic transcriptional repression [24], that dysregulate mitochondria homeostasis and induce accumulation of damaged mitochondria
Since the TGF-β response to mitochondrial DNA (mtDNA) stimulation is mediated by endocytosis (Fig 2B) and Toll-like receptor 9 (TLR9) is known to translocate to the endosome, we examined the role of TLR9 in upregulating pro-inflammatory and pro-fibrotic cytokines in the setting of PINK1 deficiency and mtDNA stimulation
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable interstitial lung disease of unknown etiology with median survival of only 2 to 3 years from the time of diagnosis [1]. Our previous work has shown that AECII in IPF lungs contain swollen and dysfunctional mitochondria secondary to deficiency of a key mediator of mitochondrial homeostasis and mitophagy, the PTEN-induced putative kinase 1 (PINK1) [4, 5]. Activation of TLR9 has been shown to be integral to the development of vascular dysfunction in hypertension, heart failure secondary to myocarditis and liver fibrosis in animal models [11,12,13] suggesting that TLR9 signaling plays a role in mediating pathologic responses to released mtDNA as a danger-associated molecular patterns (DAMPs). Increased levels of circulating mtDNA are associated with tissue injury and disease [14,15,16,17], suggesting that mitochondrial DAMPs play a role in the development or severity of human disease [14]. Circulating mtDNA has been proposed as a predictor of mortality in IPF [18]
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