NEW OXPHOS REGULATING COMPOUND – AUPHOS – INCREASES MITOCHONDRIAL COMPLEXES EXPRESSION IN MURINE AND HUMAN INTESTINAL EPITHELIAL CELLS

Abstract INTRODUCTION Mitochondrial dysfunction in intestinal epithelial cells (IEC) is a critical driver the failure to heal chronic ulceration IBD(1). OXPHOS important for differentiation and cell polarity repairing IEC(2,3). The development of new IBD drugs that improve mitochondria function would potentially accelerate mucosal repair enhance overall clinical management refractory patients. For this study, we tested efficacy novel oral agent (AuPhos) localized where it increases respiration (Wempe et al CCC, 2022) mitochondrial energy production. METHODS Colonic IEC proteins from control AuPhos-treated DSS mice were examined as described elsewhere 2022). Both human biopsy tissues with reduced [VilCre/mTmG/TFAMfl/fl (IEC-TFAM-/-)](Abomhya CCC incubated AuPhos (0.2; 0.5; 1 μM biopsies 0.5 mice) or vehicle 3 hrs. at +4oC rotation. N=4 mice/group. RESULTS In membranous fractions mice, increased protein expression complexes (Mito-Cpx) (V – 50%, III 52%, IV 40%). treatment decreased baseline dramatically 62%, 56%, II - 69%; 75%). complex V by 48%, 35%, 68%, 55% {A,B}. Expression transcriptional factors PGC1a Nrf2, which regulate biogenesis, nuclear 50% 43% respectively {C,D}. Mito-Cpx TFAM levels dose dependent manner {E}. normalized tissue (3h) taken attenuated (IEC-TFAM-/-). CONCLUSION two different murine models. results biochemical signaling studies suggest enhances Nrf2 are upstream TFAM, major transcription factor biogenesis. Our lab currently investigating compound means improving metabolism accelerating IBD. Kugathasan, S. al. Prediction complicated disease course children newly diagnosed Crohn’s disease: multicentre inception cohort study. Lancet389, 1710-1718, doi:10.1016/S0140-6736(1730317-3) (2017). 2 Rodriguez-Colman, M. J. Interplay between metabolic identities crypt supports stem function. Nature543, 424-427, doi:10.1038/nature21673 Schell, C. Control proliferation pyruvate metabolism. Nat Cell Biol19, 1027-1036, doi:10.1038/ncb3593