Lysocardiolipin acyltransferase regulates TGF-β mediated lung fibroblast differentiation

Schematic diagram illustrating the effects of TGF-β on LYCAT expression, mitochondrial oxidative stress, NOX4 activation and lung fibroblast to myofibroblast differentiation. TGF-β binding to TGF-β receptors stimulates phosphorylation and translocation of Smad2/3 to the nucleus and binding to Smad binding elements (SBE) in the promoter of LYCAT gene with subsequent induction of the expression of LYCAT. TGF-β binding to its receptors also activates mitochondrial superoxide production and NOX4 dependent H2O2 generation, which regulate fibroblast to myofibroblast differentiation leading to fibrosis. Further, Mito-TEMPO, a scavenger of mitochondrial superoxide, attenuated TGF-β mediated NOX4 activation and H2O2 production. Inhibition of NOX4 with GKT137831, an inhibitor of NOX4/NOX1, blocked TGF-β-induced mitochondrial H2O2 generation in lung fibroblasts. Overexpression of LYCAT in lung fibroblasts ameliorated TGF-β mediated mitochondrial superoxide formation and fibroblast to myofibroblast differentiation.256