TY - JOUR T1 - Modulation of Oxidative Phosphorylation with IM156 Attenuates Mitochondrial Metabolic Reprogramming and Inhibits Pulmonary Fibrosis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000811 SP - JPET-AR-2021-000811 AU - Robert N. Willette AU - Parth Mangrolia AU - Stephen M Pondell AU - Christopher Young Woo Lee AU - Sanghee Yoo AU - Marc S Rudoltz AU - Benjamin R Cowen AU - Dean J Welsch Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/10/01/jpet.121.000811.abstract N2 - Metabolic reprogramming of the myofibroblast plays a fundamental role in the pathogenesis of fibrosing interstitial lung diseases. Here, we characterized the in vitro and in vivo metabolic and anti-fibrotic effects of IM156, an oxidative phosphorylation (OXPHOS) modulator that acts by inhibiting Protein Complex 1 (PC1). In vitro, IM156 inhibited TGFβ-dependent increases in mitochondrial oxygen consumption rate and expression of myofibroblast markers in human pulmonary fibroblasts without altering cell viability or adding to TGF-β induced increases in the extracellular acidification rate (ECAR). IM156 significantly increased cellular AMPK phosphorylation and was 60-fold more potent than metformin. In vivo, chronic oral administration of IM156 was highly distributed to major peripheral organs (i.e. lung, liver, kidney, heart) and had significant dose-related effects on the plasma metabolome consistent with OXPHOS modulation and AMPK activation. IM156 increased glycolysis, lipolysis, β-oxidation and amino acids, and decreased free fatty acids, TCA cycle activity and protein synthesis. In the murine bleomycin model of pulmonary fibrosis, daily oral administration of IM156 administered 7 days after lung injury, attenuated body/lung weight changes, and reduced lung fibrosis and inflammatory cell infiltration. The plasma exposures of IM156 were comparable to well-tolerated doses in human studies. In conclusion, the metabolic and anti-fibrotic effects of IM156 suggest that OXPHOS modulation can attenuate myofibroblast metabolic reprogramming and support testing IM156 as a therapy for IPF and other fibrotic diseases. Significance Statement Fibrosing Interstitial Lung Diseases (FILD) have a poor prognosis and current anti-fibrotic treatments have significant limitations. This study demonstrates that attenuation of fibrogenic metabolic remodeling, by modulation of OXPHOS with IM156, prevents the myofibroblast phenotype/collagen deposition and is a potentially effective and translational anti-fibrotic strategy. ER -