Mitochondrial uncoupling protein‐2 reprograms metabolism to induce oxidative stress and myofibroblast senescence in age‐associated lung fibrosis. Issue 9 (7th August 2022) - Rangarajan, Sunad
Abstract: 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. Abstract : High constitutive levels of uncoupling protein‐2 (UCP2) are observed with aging and in the age‐related fibrotic disease, idiopathic pulmonary fibrosis (IPF). UCP2 functions as an exporter of fatty acid (FA) anions, which may account for the observed decrease in mitochondrial membrane potential of IPF myofibroblasts. Decreased coupling efficiency and fatty acid oxidation (FAO) lower ATP synthetic capacity in association with increased reactive oxygen species (ROS) production. These alterations promote induction of senescence and apoptosis resistance of myofibroblasts, hallmarks of recalcitrant and progressive fibrosis as seen in IPF.