ZFIN ID: ZDB-PUB-190822-12
Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction
Costa, R., Peruzzo, R., Bachmann, M., Montà, G.D., Vicario, M., Santinon, G., Mattarei, A., Moro, E., Quintana-Cabrera, R., Scorrano, L., Zeviani, M., Vallese, F., Zoratti, M., Paradisi, C., Argenton, F., Brini, M., Calì, T., Dupont, S., Szabò, I., Leanza, L.
Date: 2019
Source: Cell Reports   28: 1949-1960.e6 (Journal)
Registered Authors: Argenton, Francesco, Costa, Roberto, Moro, Enrico
Keywords: ER stress, SERCA, canonical Wnt signaling, colon cancer, mitochondrial ATP, mitochondrial fitness, β-catenin
MeSH Terms:
  • Adenosine Triphosphate/biosynthesis*
  • Animals
  • Cell Line
  • Down-Regulation*
  • Endoplasmic Reticulum Stress*
  • Fibroblasts/metabolism
  • Humans
  • Mitochondria/metabolism*
  • Wnt Signaling Pathway*
  • Zebrafish
PubMed: 31433973 Full text @ Cell Rep.
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.