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

Autor: Rangarajan S; Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado, Aurora, Colorado, USA., Locy ML; Division of Pulmonary and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA., Chanda D; Division of Pulmonary and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA., Kurundkar A; Division of Pulmonary and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA., Kurundkar D; Division of Pulmonary and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA., Larson-Casey JL; Division of Pulmonary and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA., Londono P; Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado, Aurora, Colorado, USA., Bagchi RA; Division of Cardiology, Department of Medicine, University of Colorado, Aurora, Colorado, USA., Deskin B; Division of Pulmonary and Critical Care, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA., Elajaili H; Cardiovascular Pulmonary Research Laboratories and Pediatric Critical Care Medicine, Department of Pediatrics, University of Colorado, Aurora, Colorado, USA., Nozik ES; Cardiovascular Pulmonary Research Laboratories and Pediatric Critical Care Medicine, Department of Pediatrics, University of Colorado, Aurora, Colorado, USA., Deshane JS; Division of Pulmonary and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA., Zmijewski JW; Division of Pulmonary and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA., Eickelberg O; Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA., Thannickal VJ; John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2022 Sep; Vol. 21 (9), pp. e13674. Date of Electronic Publication: 2022 Aug 07.
DOI: 10.1111/acel.13674
Abstrakt: 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.
(© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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