ROS signaling-induced mitochondrial Sgk1 expression regulates epithelial cell renewal

Area of Science:

• Cell Biology
• Mitochondrial Biology
• Regenerative Medicine

Background:

• Differentiated cells can reenter the cell cycle following injury or stress.
• The mechanisms governing quiescent cell reactivation remain largely unknown.

Purpose of the Study:

• To investigate the mechanisms of quiescent cell reactivation in a physiological context.
• To identify key molecular players involved in epithelial cell renewal.

Main Methods:

• Utilized a zebrafish model for studying epithelial cell reactivation.
• Employed genetic and pharmacological perturbations to analyze mitochondrial function and signaling pathways.
• Assessed mitochondrial membrane potential, reactive oxygen species (ROS) levels, and protein expression (Sgk1).

Main Results:

• Reactivated cells exhibited increased mitochondrial membrane potential and elevated mitochondrial metabolism.
• Increased mitochondrial metabolism led to higher mitochondrial ROS levels, inducing Sgk1 expression.
• Genetic deletion or inhibition of Sgk1 abolished epithelial cell reactivation in zebrafish.
• ROS-dependent mitochondrial Sgk1 expression promoted S phase entry in human breast cancer cells.
• Sgk1 was found to phosphorylate F1Fo-ATP synthase, coordinating mitochondrial activity and ATP synthesis.

Conclusions:

• Elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation.
• A conserved intramitochondrial signaling loop involving ROS and Sgk1 regulates epithelial cell renewal.
• Sgk1 plays a key role in coordinating mitochondrial function with cell cycle reentry.