Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Wnt signaling is crucial for development and implicated in cancer when dysregulated.
• The influence of mitochondrial energetic status on Wnt signaling remains uncharacterized.

Purpose of the Study:

• To investigate the link between mitochondrial ATP production and Wnt/β-catenin signaling.
• To elucidate the molecular mechanisms connecting mitochondrial function to Wnt pathway regulation.

Main Methods:

• Utilized compounds to modulate mitochondrial ATP production in colon cancer cells.
• Employed zebrafish reporter lines and patient-derived fibroblasts for in vivo and ex vivo studies.
• Assessed endoplasmic reticulum (ER) stress markers and calcium uptake.

Main Results:

• Decreased mitochondrial ATP production specifically downregulated Wnt/β-catenin signaling in vitro and in vivo.
• Fibroblasts from GRACILE syndrome patients and a corresponding zebrafish model exhibited reduced Wnt signaling.
• Identified a mitochondria-Wnt axis: reduced ATP leads to impaired ER calcium uptake, ER stress, and Wnt inhibition.
• Restoration of ATP levels or inhibition of ER stress reactivated Wnt signaling.

Conclusions:

• Mitochondrial energetic metabolism directly influences Wnt pathway activity.
• A novel axis links mitochondrial ATP levels to Wnt signaling via ER stress.
• This mechanism offers potential therapeutic targets for pathologies involving Wnt pathway dysregulation.