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

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 1

Mitochondrial accumulation in AECIIs from dense fibrotic areas in IPF lungs.

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Mitochondrial accumulation in AECIIs from dense fibrotic areas in IPF lu...
(A) Representative immunofluorescence using anti–SP-C (AECII marker; green) and anti–ATP synthase (mitochondrial marker; red) antibodies, showing mitochondrial accumulation in hyperplasic AECIIs from honeycombs in IPF lung (n = 7 per group). Representative cells (asterisks) are shown in detail in the insets. Scale bars: 10 μm. (B–E) Representative immunohistochemistry images (n = 6) in consecutive sections from IPF (B–D) and donor control (E) lungs using anti–SP-C and anti-TOM20 (mitochondrial marker) antibodies. Epithelial cells from honeycomb areas (B and C) showed positive staining for both markers. Epithelial cells from areas with mild fibrosis (D) and donor control lung (E) showed less positive signal for the mitochondrial marker. Note the high positivity for TOM20 in macrophages located in alveolar spaces in donor control lung. Scale bars: 50 μm. (F) Semiquantitative scoring of SP-C/ATP synthase double-positive cells as a percentage of total SP-C–stained cells from 5 cases. MMF, mild moderated fibrosis; HC, honeycomb; DF, dense fibrosis. Data represent mean ± SEM. *P < 0.01 vs. normal, #P < 0.01 as indicated, 1-way ANOVA with post-hoc Bonferroni. (G) Representative images (n = 3) of immunohistochemistry analyses in consecutive sections from IPF lungs using BiP (ER stress marker), anti–SP-C, and anti-TOM20 antibodies. Arrows denote SP-C–positive cells on mild fibrosis cases. Scale bars: 50 μm.