Department of Biology, University of Padova, Padova, Italy.
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Cell Rep. 2019 Aug 20;28(8):1949-1960.e6. doi: 10.1016/j.celrep.2019.07.050.
Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondrial energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/β-catenin signaling in vitro in colon cancer cells and in vivo in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondrial ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondrial energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologies.
Wnt 信号通路影响着基本的发育途径，而异常激活则会促进癌症的发展。Wnt 信号通路受多种因素的调节，但线粒体能量状态是否会影响 Wnt 信号通路尚不清楚。本研究表明，亚致死浓度的不同化合物可特异性降低体外结肠癌细胞和体内斑马鱼报告基因系中的 Wnt/β-catenin 信号通路。相应地，GRACILE 综合征患者的成纤维细胞和生成的斑马鱼模型导致 Wnt 信号通路减少。我们鉴定出一个线粒体-Wnt 信号轴，其中线粒体 ATP 的减少会减少内质网（ER）中的钙摄取，导致内质网应激并损害 Wnt 信号通路。反过来，ATP 水平的恢复或内质网应激的抑制会恢复 Wnt 活性。这些发现揭示了一种将线粒体能量代谢与 Wnt 通路的控制联系起来的机制，该机制可能对多种病理状况有益。
