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 6

ER stress stimulation recapitulates aging-associated susceptibility to lung fibrosis.

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ER stress stimulation recapitulates aging-associated susceptibility to l...
(A) Representative TEM (n = 4) of lungs from young and old mice at 0 (naive) and 15 days after MHV68 infection. Scale bars: 500 nm. (B) Representative TEM (n = 4) of AECIIs from young mice treated with TM only (2 μg/mouse) or TM (2 μg/mouse) followed by MHV68 infection 48 hours later. Scale bars: 500 nm. (C) Quantitative morphometry showed increased frequency of large mitochondria in young infected AECIIs when pretreated with TM. (D) Number of mitochondria per AECII (from TEM images) of MHV68-infected mice. Old mice and young TM-pretreated mice showed high numbers of mitochondria. (E) mtDNA/gDNA in lung samples showed increased mitochondrial mass after MHV68 infection in old mice and with TM treatment in young mice. (F) Representative Masson trichrome staining from lungs at day 15 after MHV68 infection, showing increased pneumonitis and collagen deposition (blue) in old mice and young TM-pretreated mice. Scale bars: 50 μm. (G) Relative change in collagen deposition (assessed by hydroxyproline level) upon MHV68 infection. (H) Relative change in Tgfb transcription upon MHV68 infection. Data represent mean ± SEM (D, E, G, and H). *P < 0.05, **P < 0.01, 2-tailed Student’s t test (C) or 1- (D, E, right, G, and H) or 2-way (E, left) ANOVA with post-hoc Bonferroni.