Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

Cell Reports. 2019;28(8):1949-1960.e6

 

Journal Homepage

Journal Title: Cell Reports

ISSN: 2211-1247 (Online)

Publisher: Elsevier

LCC Subject Category: Science: Biology (General)

Country of publisher: Netherlands

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS


Roberto Costa (Department of Biology, University of Padova, Padova, Italy)

Roberta Peruzzo (Department of Biology, University of Padova, Padova, Italy)

Magdalena Bachmann (Department of Biology, University of Padova, Padova, Italy)

Giulia Dalla Montà (Department of Biology, University of Padova, Padova, Italy)

Mattia Vicario (Department of Biomedical Sciences, University of Padova, Padova, Italy)

Giulia Santinon (Department of Molecular Medicine, University of Padova, Padova, Italy)

Andrea Mattarei (Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy)

Enrico Moro (Department of Molecular Medicine, University of Padova, Padova, Italy)

Rubén Quintana-Cabrera (Department of Biology, University of Padova, Padova, Italy; Venetian Institute of Molecular Medicine, Padova, Padova, Italy)

Luca Scorrano (Department of Biology, University of Padova, Padova, Italy; Venetian Institute of Molecular Medicine, Padova, Padova, Italy)

Massimo Zeviani (MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK)

Francesca Vallese (Department of Biomedical Sciences, University of Padova, Padova, Italy)

Mario Zoratti (Department of Biomedical Sciences, University of Padova, Padova, Italy; CNR Institute of Neuroscience, Padova, Italy)

Cristina Paradisi (Department of Chemical Sciences, University of Padova, Padova, Italy)

Francesco Argenton (Department of Biology, University of Padova, Padova, Italy)

Marisa Brini (Department of Biology, University of Padova, Padova, Italy)

Tito Calì (Department of Biomedical Sciences, University of Padova, Padova, Italy)

Sirio Dupont (Department of Molecular Medicine, University of Padova, Padova, Italy)

Ildikò Szabò (Department of Biology, University of Padova, Padova, Italy; CNR Institute of Neuroscience, Padova, Italy; Corresponding author)

Luigi Leanza (Department of Biology, University of Padova, Padova, Italy; Corresponding author)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 31 weeks

 

Abstract | Full Text

Summary: 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 signaling and mitochondrial fitness are both important for cell fate. Costa et al. demonstrate that the reduction of mitochondrial ATP production leads to the induction of ER stress and, in turn, decreases canonical Wnt/β-catenin signaling in vitro and in vivo. Keywords: mitochondrial fitness, mitochondrial ATP, canonical Wnt signaling, β-catenin, ER stress, colon cancer, SERCA