PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis
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
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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Research Article Pulmonology

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

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 5

Stimulation of ER stress deteriorates mitochondrial function and impairs mitophagy in lung epithelial cells.

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Stimulation of ER stress deteriorates mitochondrial function and impairs...
(A) A549 cells were treated with or without TM (1 μg/ml for 24 hours), and mitochondrial mass was determined by MitoTracker Green. Induction of autophagy by serum starvation reduced mitochondrial mass in TM-treated cells. The autophagy inhibitor bafilomycin A1 increased mitochondrial mass in untreated and TM-treated cells. (B) TM induced dose-dependent depolarization of mitochondria in A549 cells (assessed by JC-1 dye staining). Depolarization was increased in the presence of bafilomycin A1, but was not affected by starvation conditions. (C) Increased doses of TM induce apoptosis of A549 cells (assessed by annexin V staining). (D) Representative Western blot analyses showing increased levels of the mitochondrial marker TOM20 and autophagy markers p62 and LC3I/LC3II in lung lysates from aging and young mice after vehicle and TM treatment (2 μg/mouse). The β-actin blot was obtained from parallel samples run on a separate gel from the TOM20 and p62 blots. (E) Density analyses of Western blots in D. Data represent mean ± SEM (A–C and E). *P < 0.05, **P < 0.01, 1- (A–C) or 2-way (E) ANOVA with post-hoc Bonferroni.