Research Article: PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Marta Bueno, Daniel Zank, Ivette Buendia-Roldán, Kaitlin Fiedler, Brenton G. Mays, Diana Alvarez, John Sembrat, Brian Kimball, Jordan K. Bullock, James L. Martin, Mehdi Nouraie, Brett A. Kaufman, Mauricio Rojas, Annie Pardo, Moisés Selman, Ana L. Mora, Partha Mukhopadhyay.


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.

Partial Text

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]. In the pathogenesis of IPF, chronic microinjury and aberrant activation of type II (AECII) epithelial cells drive accumulation of fibroblasts and myofibroblasts with exuberant deposition of extracellular matrix and abnormal remodeling [2, 3]. 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].

Our previous studies have shown that AECII of IPF patients have altered mitochondrial morphology and function associated with deficiency of PINK1 [4]. In this study, we report that low levels of PINK1 in AECII resulted in mitochondrial DNA damage and release of mtDNA. Released mtDNA was recognized by TLR9 inducing downstream TGF-β-mediated pro-fibrotic responses, as well as the well-known established inflammatory mediators for this pathway. This pro-fibrotic response was originated in AECII by a NFκB dependent mechanism and led to lung fibroblast activation. We have also shown that increased levels of circulating mtDNA are found in IPF as well as HP and ILD associated with autoimmune diseases patients. However, in bronchoalveolar fluids mtDNA was significantly increased in IPF compared to the other two ILDs, and moreover, a significant correlation between levels of plasma mtDNA and disease severity was found only in IPF patients.




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