Open AccessMitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts
Author(s) -
Schuliga Michael,
Pechkovsky Dmitri V,
Read Jane,
Waters David W,
Blokland Kaj E C,
Reid Andrew T,
Hogaboam Cory M,
Khalil Nasreen,
Burgess Janette K,
Prêle Cecilia M,
Mutsaers Steven E,
Jaffar Jade,
Westall Glen,
Grainge Christopher,
Knight Darryl A
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13855
Subject(s) - senescence , idiopathic pulmonary fibrosis , mitochondrion , superoxide , dna damage , oxidative stress , microbiology and biotechnology , biology , cancer research , chemistry , medicine , endocrinology , lung , biochemistry , dna , enzyme
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 ‐ LF s). Primary cultures of IPF ‐ LF s exhibited an intensified DNA damage response ( DDR ) and were more senescent than age‐matched fibroblasts from control donors (Ctrl‐ LF s). Furthermore, IPF ‐ LF s exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA , stress and activation of mTORC 1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl‐ LF s, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF ‐ LF s. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl‐ LF s, but not IPF ‐ LF s. Inhibition of mTORC 1, 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, mTORC 1 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.