Inhibition of BRD4 Promotes Pexophagy by Increasing ROS and ATM Activation

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Autophagy is crucial for cellular quality control by degrading damaged or unnecessary components.
• Peroxisomal autophagy (pexophagy) is a specific type of autophagy, but its regulatory mechanisms are not well understood.

Purpose of the Study:

• To identify novel inducers of pexophagy.
• To elucidate the molecular mechanisms by which pexophagy is regulated.

Main Methods:

• Chemical library screening to identify pexophagy inducers.
• Treatment with BRD4 inhibitors (e.g., molibresib) in cell lines (HeLa, RPE).
• Assessment of peroxisome degradation and cellular organelle integrity.
• Analysis of ATG7-dependency, reactive oxygen species (ROS) production, and ATM activation.

Main Results:

• Molibresib, a BRD4 inhibitor, was identified as a novel pexophagy inducer.
• BRD4 inhibition selectively promoted the degradation of peroxisomes, sparing other organelles.
• Pexophagy induced by molibresib was dependent on ATG7.
• Molibresib treatment increased ROS production and activated ATM.
• Inhibition of ROS or ATM attenuated molibresib-induced pexophagy.

Conclusions:

• BRD4 inhibition is a novel strategy to induce pexophagy.
• The mechanism involves increased ROS production and subsequent ATM activation.
• These findings shed light on the regulation of pexophagy and cellular quality control.