ATF3 regulates PINK1 transcription in lung epithelial cells of the aging lung

Abstract

Aging is associated with increased susceptibility to Idiopathic pulmonary fibrosis (IPF). Alveolar type II cells (AECII) in IPF lung have marked accumulation of dysmorphic and dysfunctional mitochondria, associated with low expression of the PTEN-induced putative kinase 1 (PINK1). These mitochondrial abnormalities can be recapitulated in mice combining advancing age and ER (endoplasmic reticulum) stress stimulation and in PINK1 deficient mice. However, the molecular mechanism linking ER stress and PINK1 expression are still unknown. PINK1 transcription is significantly reduced in A549 cells exposed to tunicamycin (TM), a well-known ER stressor. This reduction is reversed in the presence of actinomycin D suggesting transcriptional repression of PINK1 by ER stress. Also, TM induces expression of genes involved in the unfolded protein response (UPR) including the activating transcription factor 3 (ATF3), a member of the ATF/CREB family that can act as a transcriptionalrepressor. Analyses of the human PINK1 promoter reveals the presence of two ATF3 consensus sites upstream of the transcriptional starting site. Depletion of ATF3 in cells showed reduced ATF3 expression and increased PINK1 transcript levels at baseline and after TM treatment. Immunohistochemistry studies found that ATF3 is highly expressed in aging human lungs and AECII lining honeycomb areas of IPF lungs. These data are the first to link ATF3 to PINK1 expression in any system and suggest that ER stress, via ATF3, can regulate mitochondrial homeostasis by repression of PINK1 gene transcription. Also, strategies designed to modulate PINK1 or ATF3 expression might lessen severity of pulmonary fibrosis, especially in the context of the aging lung.