Publication

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga, M., Pechkovsky, D. V., Read, J., Waters, D. W., Blokland, K. E. C., Reid, A. T., Hogaboam, C. M., Khalil, N., Burgess, J. K., Prêle, C. M., Mutsaers, S. E., Jaffar, J., Westall, G., Grainge, C. & Knight, D. A. Dec-2018 In : Journal of cellular and molecular medicine. 22, 12, p. 5847-5861 15 p.

Research output: Contribution to journalArticle

  • Michael Schuliga
  • Dmitri V Pechkovsky
  • Jane Read
  • David W Waters
  • Kaj E C Blokland
  • Andrew T Reid
  • Cory M Hogaboam
  • Nasreen Khalil
  • Janette K Burgess
  • Cecilia M Prêle
  • Steven E Mutsaers
  • Jade Jaffar
  • Glen Westall
  • Christopher Grainge
  • Darryl A Knight

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.

Original languageEnglish
Pages (from-to)5847-5861
Number of pages15
JournalJournal of cellular and molecular medicine
Volume22
Issue number12
StatePublished - Dec-2018

    Keywords

  • cyclin-dependent kinase inhibitors, fibroblasts, idiopathic pulmonary fibrosis, mechanistic target of rapamycin complex 1, mitochondria, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, rapamycin, reactive oxygen species and mitoTEMPO, adult, article, controlled study, DNA damage response, enzyme activity, fibrosing alveolitis, homeostasis, human, human cell, lung fibroblast, mitochondrion, phenotype, primary culture, senescence, signal transduction, stress, antioxidant, cyclin dependent kinase inhibitor, endogenous compound, etoposide, mammalian target of rapamycin complex 1, peroxisome proliferator activated receptor gamma coactivator 1alpha, reactive oxygen metabolite, rotenone, superoxide

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