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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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 4

Impaired mitochondrial function and fission/fusion dynamics in AECIIs with age.

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Impaired mitochondrial function and fission/fusion dynamics in AECIIs wi...
(A) Mitochondrial respiration parameters in isolated primary AECIIs from young and old C57BL/6 mice with vehicle control or TM treatment (1 μg/ml for 1 hour). (B) Representative TEM (n = 3 per group) showing enlarged mitochondria but preserved structure in AECIIs from naive old mice. Boxed regions are shown enlarged at right. Scale bars: 500 nm. (C) Quantitative morphometry showed significantly increased frequency of large mitochondria in AECIIs from naive old mice (n ≥ 100 per condition). (D) Representative TEM (n = 3 per group) showing enlarged mitochondria in AECIIs from TM-treated young and old mice. Boxed regions are shown enlarged at right. Scale bars: 500 nm. (E) Morphometry showed increased frequency of large mitochondria in young and old AECIIs after TM treatment (n ≥ 100 per condition). (F) Area of AECII mitochondria and percentage of abnormal mitochondria (swollen with evidence of severely disrupted cristae over all mitochondria) from TEM images. (G) Representative Western blot membranes showing higher expression levels of mitochondrial fusion modulators (p-DRP1, MTF2, OPA1, and MTF1) in lungs from young and old mice treated with TM. (H) Density analyses of Western blots for fusion and fission mitochondrial modulators. Data represent mean ± SEM (A, F, and H). *P < 0.05, **P < 0.01 vs. young; #P < 0.05, ##P < 0.01 as indicated, 2-tailed Student’s t test (A, C, and E) or 1-way ANOVA with post-hoc Bonferroni (F and H).