Hyuk Soo Eun M.D and Won-Il Jeong D.V.M., Ph.D.
Laboratory of Liver Research Graduate School of Medical Science and Engineering, Korea Advanced Institutes of Science and Technology, Daejeon, Republic of Korea
Address correspondence to Won-Il Jeong D.V.M., Ph.D.
Recently, Xu det al. published an interesting article titled ' NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activiation' in the Journal of Clinical Investigation (2015; 125; 1579-1590). In the reported study, the authors demonstrate that in response to inflammatory signals in alcoholic steatohepatitis (ASH), macrophages, but not Kupffer cells, are reprogrammed to become proinflammatory (M1) macrophages through dual Notch signaling pathways, in which the NOTCH1 intracellular domain (NICD1) translocates into the nucleus and mitochondria to upregulate the expression of M1 genes (e.g., inducible nitric oxide synthase, NOS2) and mitochondrial respiratory complex-related genes (e.g., pyruvate dehydrogenase phosphatase, PDP).1 This work also demonstrates that Notch-mediated activation of mitochondrial oxidative phosphorylation (OXPHOS) increases ATP production through the electron transport chain (ETC) complexes where the majority of mitochondrial reactive oxygen species (mtROS) are generated. mtROS also stimulate nuclear factor-κB (NF-κB) and stabilize hypoxia-inducible factor-1α (HIF-1α), which regulate the transcription of NOS2. Thus, these results suggest the existence of a pathway wherein inhibition of Notch signaling may be a potential therapeutic target for ameliorating ASH (Fig. 1).