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Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in
Prerona Bora1,2, Mashiat Zaman3,2, Samantha Oviedo1,4
1Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037.
Biorxiv : the Preprint Server for Biology
|July 16, 2025
Summary
New drugs parogrelil and MBX-2982 activate the integrated stress response (ISR) to improve mitochondrial function in Charcot-Marie-Tooth Type 2A (CMT2A) disease models.
Area of Science:
- Mitochondrial biology
- Neuroscience
- Pharmacology
Background:
- Pathogenic variants in Mitofusin-2 (MFN2) cause Charcot-Marie-Tooth Type 2A (CMT2A), leading to mitochondrial dysfunction.
- Current therapies do not address the underlying mitochondrial defects in CMT2A.
Purpose of the Study:
- To identify compounds that activate the integrated stress response (ISR) to mitigate MFN2 deficiency-related mitochondrial dysfunction.
- To evaluate the therapeutic potential of ISR activators in CMT2A.
Main Methods:
- Drug repurposing screen to identify ISR activators.
- Investigated the OMA1-DELE1-HRI signaling axis.
- Assessed mitochondrial morphology, motility, mitochondrial-ER contacts (MERCs), and respiration in MFN2-deficient cells.
Main Results:
- Identified parogrelil and MBX-2982 as selective ISR activators.
- ISR activation promoted adaptive mitochondrial remodeling and protected against insults.
- Parogrelil treatment restored mitochondrial morphology, motility, MERCs, and respiration in MFN2-deficient cells.
Conclusions:
- Pharmacologic activation of the ISR via HRI is a promising therapeutic strategy for CMT2A.
- This approach may also benefit other pathologies linked to MFN2 deficiency.
