Mitochondrial uncoupling protein-2 reprograms metabolism to induce oxidative stress and myofibroblast senescence in age-associated lung fibrosis

Aging Cell. 2022 Sep;21(9):e13674. doi: 10.1111/acel.13674. Epub 2022 Aug 7.


Mitochondrial dysfunction has been associated with age-related diseases, including idiopathic pulmonary fibrosis (IPF). We provide evidence that implicates chronic elevation of the mitochondrial anion carrier protein, uncoupling protein-2 (UCP2), in increased generation of reactive oxygen species, altered redox state and cellular bioenergetics, impaired fatty acid oxidation, and induction of myofibroblast senescence. This pro-oxidant senescence reprogramming occurs in concert with conventional actions of UCP2 as an uncoupler of oxidative phosphorylation with dissipation of the mitochondrial membrane potential. UCP2 is highly expressed in human IPF lung myofibroblasts and in aged fibroblasts. In an aging murine model of lung fibrosis, the in vivo silencing of UCP2 induces fibrosis regression. These studies indicate a pro-fibrotic function of UCP2 in chronic lung disease and support its therapeutic targeting in age-related diseases associated with impaired tissue regeneration and organ fibrosis.

Keywords: UCP2; cellular senescence; fibroblast; fibrosis; myofibroblast; oxidative stress; uncoupling protein-2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Animals
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Idiopathic Pulmonary Fibrosis* / metabolism
  • Lung / metabolism
  • Mice
  • Myofibroblasts* / metabolism
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism
  • Uncoupling Protein 2* / genetics
  • Uncoupling Protein 2* / metabolism


  • Reactive Oxygen Species
  • UCP2 protein, human
  • Ucp2 protein, mouse
  • Uncoupling Protein 2