Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

被引：71

作者：

Costa, Roberto ^{[1
]}

Peruzzo, Roberta ^{[1
]}

Bachmann, Magdalena ^{[1
]}

Dalla Monta, Giulia ^{[1
]}

Vicario, Mattia ^{[2
]}

Santinon, Giulia ^{[3
]}

Mattarei, Andrea ^{[4
]}

Moro, Enrico ^{[3
]}

Quintana-Cabrera, Ruben ^{[1
,5
,9
]}

Scorranot, Luca ^{[1
,5
]}

Zeviani, Massimo ^{[6
,10
]}

Vallese, Francesca ^{[2
]}

Zoratti, Mario ^{[2
,7
]}

Paradisi, Cristina ^{[8
]}

Argenton, Francesco ^{[1
]}

Brini, Marisa ^{[1
]}

Cali, Tito ^{[2
]}

Dupont, Sirio ^{[3
]}

Szabo, Ildiko ^{[1
,7
]}

Leanza, Luigi ^{[1
]}

机构：

[1] Univ Padua, Dept Biol, Padua, Italy

[2] Univ Padua, Dept Biomed Sci, Padua, Italy

[3] Univ Padua, Dept Mol Med, Padua, Italy

[4] Univ Padua, Dept Pharmaceut & Pharmacol Sci, Padua, Italy

[5] Venetian Inst Mol Med, Padua, Italy

[6] Univ Cambridge, MRC, Mitochondria Biol Unit, Cambridge, England

[7] CNR, Inst Neurosci, Padua, Italy

[8] Univ Padua, Dept Chem Sci, Padua, Italy

[9] Univ Salamanca, CSIC, Inst Funct Biol & Genom, Salamanca, Spain

[10] Univ Padua, Dept Neurosci, Padua, Italy

来源：

CELL REPORTS | 2019年 / 28卷 / 08期

关键词：

ENDOPLASMIC-RETICULUM; CA2+ CONCENTRATION; CANCER-CELLS; COMPLEX; ACTIVATION; INHIBITION; MUTATIONS; PATHWAY; YAP/TAZ; BIOGENESIS;

D O I：

10.1016/j.celrep.2019.07.050

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 mitochondria! energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/beta-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 mitochondria! 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 mitochondria! energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologies.

引用

页码：1949 / +

页数：18

共 77 条

[51] In vivo Wnt signaling tracing through a transgenic biosensor fish reveals novel activity domains [J].