ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion.

Area of Science:

• Biomedical Engineering
• Regenerative Medicine
• Cell Biology

Background:

• Cranial suture expansion therapy effectiveness depends on bone regeneration.
• Preventing post-expansion relapse requires understanding bone remodeling mechanisms.

Purpose of the Study:

• Investigate mechanisms of bone remodeling during suture expansion and relapse.
• Identify signaling pathways governing mesenchymal stem cell response to mechanical stimuli.

Main Methods:

• In vitro cell stretching assays.
• Analysis of endoplasmic reticulum (ER) stress and mitochondrial dynamics.
• Assessment of protein kinase R-like ER kinase (PERK) and transcription factor EB (TFEB) signaling.
• Pharmacological manipulation of mitophagy.

Main Results:

• In vitro stretching enhanced mesenchymal stem cell osteogenesis via ER stress-mediated mitochondrial activity.
• Force-induced ER stress activated PERK at the ER-mitochondria interface, triggering TFEB nuclear translocation.
• A two-phase regulation of mitochondrial biogenesis and mitophagy by the ER stress/p-PERK/TFEB cascade was observed.
• Disruption of this cascade led to impaired mitophagy, mitochondrial dysfunction, and relapse.

Conclusions:

• The ER stress/p-PERK/TFEB pathway orchestrates sequential mitochondrial biogenesis and mitophagy under mechanical stretch.
• This signaling ensures antioxidative capacity and osteogenic potential in cranial suture tissues.
• Targeting mitophagy can mitigate relapse and enhance bone regeneration in cranial suture expansion therapy.