In nematode Caenorhabditis elegans, an intestinal signaling cascade in canonical Wnt/beta-catenin signaling pathway, including beta-catenin transcriptional factor BAR-1, has been identified to be involved in the control of response to simulated microgravity. However, the downstream target(s) of BAR-1 in regulating the response to simulated microgravity are still unclear. In this study, we found that BAR-1 and its direct target of Wnt effector POP-1 functioned upstream of a Meis TALE-class transcription factor UNC-62 to regulate the response to simulated microgravity. Moreover, UNC-62 regulated the response to simulated microgravity by suppressing the function of FOXO transcriptional factor DAF-16 and its target (mitochondria) Mn-SOD/SOD-3) in insulin signaling pathway. Therefore, canonical Wnt/beta-catenin signaling mediates a protective intestinal response to simulated microgravity by inducing a nucleus-mitochondria communication. Our results provide an important molecular basis for intestinal Wnt/beta-catenin signaling in response to simulated microgravity in organisms. (C) 2019 Elsevier Inc. All rights reserved.