Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction.

TitleImpaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction.
Publication TypeJournal Article
Year of Publication2019
AuthorsCosta, R, Peruzzo, R, Bachmann, M, Montà, GDalla, 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, Szabó, I, Leanza, L
JournalCell Rep
Volume28
Issue8
Pagination1949-1960.e6
Date Published2019 08 20
ISSN2211-1247
KeywordsAdenosine Triphosphate, Animals, Cell Line, Down-Regulation, Endoplasmic Reticulum Stress, Fibroblasts, Humans, Mitochondria, Wnt Signaling Pathway, Zebrafish
Abstract

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.

DOI10.1016/j.celrep.2019.07.050
Alternate JournalCell Rep
Citation Key10.1016/j.celrep.2019.07.050
PubMed ID31433973