Reply to Kobayashi et al.: Adenine Nucleotide Translocases and Cellular Senescence in Idiopathic Pulmonary Fibrosis

From the Authors:

We appreciate the positive and insightful comments from Kobayashi and colleagues highlighting our publication (1). The authors of the letter accurately point out that our study is limited to epithelial cells, and indeed other cell types play a crucial role in idiopathic pulmonary fibrosis (IPF) and senescence. Although we show that adenine nucleotide translocase 1 (ANT1; SLC25A4) expression is decreased in whole-lung tissue and specifically in alveolar type 2 cells of patients with IPF, other cell types may also have dysregulation of ANT1. This presents an interesting focus for future studies to define how ANT-mediated mitochondrial function impacts cellular behavior and contributes to disease pathogenesis. Furthermore, it may shed light on how ANTs can be used as a therapeutic target in epithelial cells or if the potential is broader.

Senescence-associated secretory phenotype (SASP) is known to yield paracrine signaling effects upon a variety of disparate cell types (2). SASP related to mitochondrial dysfunction has been shown to differ from that of other types of senescence induction (3). We found upregulation of the matrix metalloproteinase 12, GDF-15, and vascular endothelial growth factor in the lavage fluid of Ant1 knockout mice. It would be interesting to explore how SASP patterns diverge with mitochondrial dysfunction and whether certain combinations of SASP are critical to IPF development. Furthermore, it is unclear whether the susceptibility to senescence is due primarily to changes in mitochondrial metabolism and redox balance or to other nonmetabolic functions of ANT1. We hope our study will provide useful insights into the role of ANT-dependent senescence in not just IPF but also other lung disease contexts such as chronic obstructive pulmonary disease.