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PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis
Marta Bueno, … , Charleen T. Chu, Ana L. Mora
Marta Bueno, … , Charleen T. Chu, Ana L. Mora
Published December 22, 2014
Citation Information: J Clin Invest. 2015;125(2):521-538. https://doi.org/10.1172/JCI74942.
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Research Article Pulmonology Article has an altmetric score of 23

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

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Abstract

Although aging is a known risk factor for idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms that underlie the effects of advancing age remain largely unexplained. Some age-related neurodegenerative diseases have an etiology that is related to mitochondrial dysfunction. Here, we found that alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. These mitochondrial abnormalities in AECIIs of IPF lungs were associated with upregulation of ER stress markers and were recapitulated in normal mice with advancing age in response to stimulation of ER stress. We found that impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1). Knockdown of PINK1 expression in lung epithelial cells resulted in mitochondria depolarization and expression of profibrotic factors. Moreover, young PINK1-deficient mice developed similarly dysmorphic, dysfunctional mitochondria in the AECIIs and were vulnerable to apoptosis and development of lung fibrosis. Our data indicate that PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, and promotes fibrosis in the aging lung.

Authors

Marta Bueno, Yen-Chun Lai, Yair Romero, Judith Brands, Claudette M. St. Croix, Christelle Kamga, Catherine Corey, Jose D. Herazo-Maya, John Sembrat, Janet S. Lee, Steve R. Duncan, Mauricio Rojas, Sruti Shiva, Charleen T. Chu, Ana L. Mora

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Figure 3

Defective autophagy in AECIIs from IPF lungs.

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Defective autophagy in AECIIs from IPF lungs.
(A) Representative immunos...
(A) Representative immunostaining of lung sections from donor and IPF patients using anti-LC3 (red; autophagosomal marker) and anti–ATP synthase (green; mitochondrial marker) antibodies. Yellow puncta denote colocalization. Scale bars: 10 μm. (B) x-z coordinate image of z stack of merged LC3 and ATP synthase image of the IPF lung section in A. Partial colocalization was seen for the mitochondrial and autophagosomal markers (arrow). (C) Western blot analyses of p62 and LC3I/LC3II in isolated AECIIs from donor age-matched control and IPF lungs. Each lane represents an individual AECII preparation. Blots were stripped and reblotted using an anti–β-actin antibody as loading control. Results are also quantified below. Data represent mean ± SEM. *P < 0.05, unpaired, 2-tailed Student’s t test. (D) Representative immunostaining of donor and IPF patient lung sections using anti–SP-C (green) and anti-p62 (red). Yellow indicates colocalization of the markers. Scale bars: 10 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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