- Title
- Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts
- Creator
- Schuliga, Michael; Pechkovsky, Dmitri V.; Mutsaers, Steven E.; Jaffar, Jade; Westall, Glen; Grainge, Christopher; Knight, Darryl A.; Read, Jane; Waters, David W.; Blokland, Kaj E. C.; Reid, Andrew T.; Hogaboam, Cory M.; Khalil, Nasreen; Burgess, Janette K.; Prêle, Cecilia M.
- Relation
- Journal of Cellular and Molecular Medicine Vol. 22, Issue 12, p. 5847-5861
- Publisher Link
- http://dx.doi.org/10.1111/jcmm.13855
- Publisher
- Wiley-Blackwell
- Resource Type
- journal article
- Date
- 2018
- Description
- 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.
- Subject
- cyclin-dependent kinase inhibitors; fibroblasts; idiopathic pulmonary fibrosis; mechanistic target of rapamycin complex 1; peroxisome proliferator-activated receptor gamma coactivator 1-alpha; rapamycin; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1459525
- Identifier
- uon:45701
- Identifier
- ISSN:1582-1838
- Rights
- © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Language
- eng
- Full Text
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