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 2

Accumulation of dysmorphic and dysfunctional mitochondria in AECIIs from IPF lungs.

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Accumulation of dysmorphic and dysfunctional mitochondria in AECIIs from...
(A) Representative TEM (n = 4 per group) in donor and IPF AECIIs (identified by the presence of lamellar bodies). Boxed regions are shown enlarged at right. Scale bars: 500 nm. (B) Quantitative analyses of morphometric data from TEM images. (C) Frequency of mitochondria sizes in donor control and IPF lungs obtained from TEM images. (D) Isolated lung mitochondria showed reduced mitochondrial complex I and complex IV activity in IPF patients relative to age-matched donor controls. (E) Representative TEM (n = 3 per group) in AECIIs from young (<50 years) and older (>50 years) donor control lungs. Boxed regions are shown enlarged at right. Scale bars: 500 nm. (F) Frequency of mitochondria sizes and mitochondrial area from AECIIs in young and old donor controls (obtained from TEM images). (G) No significant difference in number of mitochondria per cell (obtained from TEM images) between young and old donor control AECIIs. (H) Percentage of abnormal mitochondria (swollen with evidence of severely disrupted cristae over all mitochondria) (obtained from TEM images). (I) Increased mitochondrial mass in IPF lungs, assessed by mtDNA/gDNA ratio. (J) Mitochondrial mass, assessed by mtDNA/gDNA ratio, in isolated AECIIs and lung fibroblasts from donor and IPF lungs. Data represent mean ± SEM (B, D, and F–J). *P < 0.05, **P < 0.01, unpaired, 2-tailed Student’s t test (B–D, F, G,and J) or 1-way ANOVA with post-hoc Bonferroni (H and I).