Journal article
Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts
Journal of Cellular and Molecular Medicine, Vol.22(12), pp.5847-5861
2018
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.
Details
- Title
- Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts
- Authors/Creators
- M. Schuliga (Author/Creator)D.V. Pechkovsky (Author/Creator)J. Read (Author/Creator)D.W. Waters (Author/Creator)K.E.C. Blokland (Author/Creator)A.T. Reid (Author/Creator)C.M. Hogaboam (Author/Creator)N. Khalil (Author/Creator)J.K. Burgess (Author/Creator)C.M. Prêle (Author/Creator)S.E. Mutsaers (Author/Creator)J. Jaffar (Author/Creator)G. Westall (Author/Creator)C. Grainge (Author/Creator)D.A. Knight (Author/Creator)
- Publication Details
- Journal of Cellular and Molecular Medicine, Vol.22(12), pp.5847-5861
- Publisher
- Wiley
- Identifiers
- 991005540473407891
- Copyright
- © 2018 The Authors.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.208 Vasculitis & Autoimmune Disorders
- 1.208.1262 Idiopathic Pulmonary Fibrosis
- Web Of Science research areas
- Cell Biology
- Medicine, Research & Experimental
- ESI research areas
- Molecular Biology & Genetics