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 7

Downregulation of PINK1 expression in AECIIs and lungs from aging and TM-treated mice.

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Downregulation of PINK1 expression in AECIIs and lungs from aging and TM...
(A) Microarray analyses of the LGRC cohort showed significantly decreased PINK1 expression in IPF patients (#P < 0.0001 vs. control). Data are presented as box-and-whisker plots, with horizontal bars representing medians, top whisker representing maximal expression, and bottom whisker representing the 5th percentile. (B) Significant reduction of PINK1 transcripts, assessed by quantitative RT-PCR, in whole IPF lungs. (C) Significant reduction of PINK1 transcripts in isolated IPF AECIIs. (D) Immunoblot of lysates of isolated AECIIs from donor control and IPF lungs showing lower levels of full-length (FL) PINK1 in IPF lungs. (E) PINK1 transcript levels, assessed by quantitative RT-PCR, in isolated lung fibroblasts from donor control and IPF patients. (F) Representative immunoblot of isolated lung fibroblasts from young (<50 years) and old (>50 years) donor controls and IPF patients, showing similar protein levels of full-length PINK1 and isoforms ΔN1 and ΔN2. (G) Quantitative RT-PCR showed diminished Pink1 expression in murine lungs with age and after TM treatment. (H) In vitro TM treatment diminished PINK1 expression in A549 cells. Data represent mean ± SEM (B, C, E, G, and H). *P < 0.05, **P < 0.01, unpaired 2-tailed Student’s t test (B, C, and E) or 1- (H) or 2-way (G) ANOVA with post-hoc Bonferroni.