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PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis.

The Journal of clinical investigation (2015-01-07)
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
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.

MATERIALS
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