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 10

Mitochondrial dysfunction and increased cell apoptosis in PINK1-deficient mice.

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Mitochondrial dysfunction and increased cell apoptosis in PINK1-deficien...
(A) Complex I and complex IV activity, both basal and after MHV68 infection, was reduced in Pink1–/– versus Pink1+/+ lung mitochondria. CS, citrate synthase. (B) Mitochondrial mass (assessed by mtDNA/gDNA ratio) in lungs of infected Pink1+/+, Pink1+/–, and Pink1–/– mice. (C) Representative in situ TUNEL assay in lung sections at day 15 after MHV68 infection. Note the increase in positive signal (brown) in PINK1-deficient lungs. Scale bars: 50 μm. (D) Semiquantitative analyses showed significantly higher TUNEL-positive signal in PINK1-deficient versus control mice. (E and F) Immunoblot analyses in whole lung lysates from naive (E) and MHV68-infected (F) Pink1+/+, Pink1+/–, and Pink1–/– mice for BAX, OPA1, and the autophagic markers LC3I/LC3II and p62. Blots were stripped and reblotted with β-actin for loading normalization. Each lane represents an individual mouse. (G) Density analyses of LC3 and p62. Data represent mean ± SEM (A, B, D, and G). #P < 0.05 vs. Pink1+/+; *P < 0.05; 1- (B and D) or 2-way (A and G) ANOVA with post-hoc Bonferroni.