1. Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts
- Author
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Cecilia M. Prêle, David W Waters, Michael Schuliga, Darryl A. Knight, Jade Jaffar, Cory M. Hogaboam, Christopher Grainge, Kaj E C Blokland, Nasreen Khalil, Jane Read, Steven E. Mutsaers, Dmitri V. Pechkovsky, Janette K. Burgess, Glen P. Westall, Andrew T. Reid, Groningen Research Institute for Asthma and COPD (GRIAC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
0301 basic medicine ,senescence ,antioxidant ,endogenous compound ,mTORC1 ,reactive oxygen metabolite ,Mitochondrion ,DNA damage response ,etoposide ,cyclin‐dependent kinase inhibitors ,rotenone ,cyclin-dependent kinase inhibitors ,stress ,chemistry.chemical_compound ,homeostasis ,peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha ,mitochondrion ,Myofibroblasts ,Lung ,Cellular Senescence ,primary culture ,Superoxide ,adult ,article ,respiratory system ,idiopathic pulmonary fibrosis ,mechanistic target of rapamycin complex 1 ,enzyme activity ,Cell biology ,mitochondria ,medicine.anatomical_structure ,Molecular Medicine ,Original Article ,superoxide ,Signal transduction ,signal transduction ,Senescence ,phenotype ,DNA damage ,Down-Regulation ,cyclin dependent kinase inhibitor ,peroxisome proliferator-activated receptor gamma coactivator 1-alpha ,Cyclic N-Oxides ,03 medical and health sciences ,peroxisome proliferator activated receptor gamma coactivator 1alpha ,fibroblasts ,medicine ,Humans ,controlled study ,human ,Fibroblast ,Sirolimus ,reactive oxygen species and mitoTEMPO ,rapamycin ,human cell ,Original Articles ,mammalian target of rapamycin complex 1 ,Cell Biology ,Acetylcysteine ,respiratory tract diseases ,fibrosing alveolitis ,030104 developmental biology ,chemistry ,lung fibroblast ,Biomarkers ,Homeostasis - Abstract
Increasing evidence highlights that senescence plays an important role in idiopathic pulmonary fibrosis (IPF). This study delineates the specific contribution of mitochondria and the superoxide they form to the senescent phenotype of lung fibroblasts from IPF patients (IPF‐LFs). Primary cultures of IPF‐LFs exhibited an intensified DNA damage response (DDR) and were more senescent than age‐matched fibroblasts from control donors (Ctrl‐LFs). Furthermore, IPF‐LFs exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA, stress and activation of mTORC1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl‐LFs, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF‐LFs. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl‐LFs, but not IPF‐LFs. Inhibition of mTORC1, antioxidant treatment and a mitochondrial targeting antioxidant decelerated IPF‐LF senescence and/or attenuated pharmacologically induced Ctrl‐LF senescence. In conclusion, increased superoxide production by dysfunctional mitochondria reinforces lung fibroblast senescence via prolongation of the DDR. As part of an auto‐amplifying loop, mTORC1 is activated, altering mitochondrial homoeostasis and increasing superoxide production. Deeper understanding the mechanisms by which mitochondria contribute to fibroblast senescence in IPF has potentially important therapeutic implications.
- Published
- 2018