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Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in
Prerona Bora1, Mashiat Zaman2, Samantha Oviedo1,3
1Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037.
Abstract:
Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth type 2A (CMT2A). These mutations can disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR)-the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2-deficient cells. These results demonstrate the potential for pharmacologic ISR activation through the OMA1-DELE1-HRI signaling pathway as a potential strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.
Insights
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. This ISR activation offers a potential therapeutic strategy for MFN2 deficiency disorders.
Area of Science:
- Mitochondrial biology
- Neuroscience
- Pharmacology
Background:
- Pathogenic variants in Mitofusin-2 (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A), a peripheral neuropathy.
- MFN2 deficiency disrupts mitochondrial morphology, motility, mitochondrial-ER contacts (MERCs), and respiratory function.
- Currently, no therapies exist to address MFN2-related mitochondrial dysfunction.
Purpose of the Study:
- To identify compounds that activate the integrated stress response (ISR) to mitigate mitochondrial dysfunction in MFN2 deficiency.
- To investigate the therapeutic potential of ISR activation for CMT2A and related disorders.
Main Methods:
- Drug repurposing screen to identify ISR activators.
- Utilized the OMA1-DELE1-HRI signaling axis for ISR activation.
- Assessed mitochondrial morphology, motility, MERCs, and respiration in MFN2-deficient cells.
Main Results:
- Parogrelil and MBX-2982 were identified as potent and selective ISR activators.
- ISR activation promoted adaptive mitochondrial remodeling and protected against cellular insults.
- Pharmacologic ISR activation by parogrelil restored mitochondrial tubular morphology, motility, MERCs, and enhanced respiration in MFN2-deficient cells.
Conclusions:
- Pharmacologic activation of the ISR via the OMA1-DELE1-HRI pathway is a promising therapeutic strategy.
- This approach may mitigate mitochondrial dysfunction in CMT2A and other pathologies linked to MFN2 deficiency.
