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Chemical modulation of Miro1 alleviates cell-type-specific vulnerabilities in Friedreich's ataxia
Sujyoti Chandra1, Chulhwan S Kwak1, Zehui Du1
1Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Abstract:
Friedreich's ataxia (FA) is marked by early-onset sensory neurodegeneration and cardiomyopathy. We establish a human dual-cell model of FA by differentiating sensory neurons and cardiomyocytes from the same patients, enabling parallel molecular profiling of disease-relevant cell types. Proteomic analysis reveals distinct, cell-type-specific pathway disruptions in response to frataxin deficiency. Leveraging this platform, we investigate Miro1 reducer 3 (MR3), a selective chemical probe binding Miro1, a mitochondrial outer membrane protein implicated in redox regulation in FA. MR3 treatment modulates molecular signatures in a cell-type-dependent manner, altering pathways related to cardiac contractility in cardiomyocytes and synaptic function in sensory neurons. Mechanistically, MR3 reduces mitochondrial reactive oxygen species and restores membrane potential in FA sensory neurons via potential allosteric reshaping of Miro1 protein. We expand the chemical diversity of this scaffold by conducting ligand-based virtual screening of over 3 billion compounds and identifying previously uncharacterized Miro1 ligands with improved docking and neuroprotective capacity.
Insights
Friedreich
Area of Science:
- Neuroscience and Cardiology
- Mitochondrial Biology
- Drug Discovery
Background:
- Friedreich's ataxia (FA) is a genetic disorder causing early-onset neurodegeneration and cardiomyopathy.
- Existing research lacks cell models capturing FA's dual impact on neurons and heart cells.
- Mitochondrial dysfunction and redox dysregulation are key pathological features in FA.
Purpose of the Study:
- To develop and utilize a human dual-cell model for parallel profiling of FA-relevant cell types.
- To investigate the therapeutic potential of Miro1 reducer 3 (MR3) in FA.
- To identify novel Miro1 ligands for potential FA treatment.
Main Methods:
- Established a dual-cell model differentiating patient-derived sensory neurons and cardiomyocytes.
- Performed proteomic analysis to identify cell-type-specific pathway disruptions.
- Investigated the effects of MR3, a Miro1-targeting chemical probe, on cellular pathways and mitochondrial function.
- Conducted large-scale virtual screening to discover novel Miro1 ligands.
Main Results:
- The dual-cell model revealed distinct, cell-type-specific molecular changes in FA.
- MR3 treatment modulated FA-associated pathways in both neurons and cardiomyocytes, reducing mitochondrial reactive oxygen species and restoring membrane potential in neurons.
- Virtual screening identified novel Miro1 ligands with enhanced neuroprotective capacity.
Conclusions:
- The human dual-cell model provides a powerful platform for studying FA's complex pathology.
- MR3 demonstrates cell-type-specific therapeutic effects, highlighting Miro1 as a viable drug target for FA.
- Novel Miro1 ligands offer promising avenues for future Friedreich's ataxia drug development.
