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Updated: Mar 6, 2026
In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination
Published on: January 2, 2026
Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease
Ting Zhang1, Prashant Mishra2, Bruce A Hay2
1Department of Neurology, UCLA David Geffen School of Medicine, University of California, Los Angele, United States.
Abstract:
Missense mutations of valosin-containing protein (VCP) cause an autosomal dominant disease known as inclusion body myopathy, Paget disease with frontotemporal dementia (IBMPFD) and other neurodegenerative disorders. The pathological mechanism of IBMPFD is not clear and there is no treatment. We show that endogenous VCP negatively regulates Mitofusin, which is required for outer mitochondrial membrane fusion. Because 90% of IBMPFD patients have myopathy, we generated an in vivo IBMPFD model in adult Drosophila muscle, which recapitulates disease pathologies. We show that common VCP disease mutants act as hyperactive alleles with respect to regulation of Mitofusin. Importantly, VCP inhibitors suppress mitochondrial defects, muscle tissue damage and cell death associated with IBMPFD models in Drosophila. These inhibitors also suppress mitochondrial fusion and respiratory defects in IBMPFD patient fibroblasts. These results suggest that VCP disease mutants cause IBMPFD through a gain-of-function mechanism, and that VCP inhibitors have therapeutic value.
Insights
Missense mutations in valosin-containing protein (VCP) cause IBMPFD. VCP inhibitors show therapeutic potential by suppressing mitochondrial defects and muscle damage in IBMPFD models.
Area of Science:
- Cell Biology
- Neurodegenerative Diseases
- Mitochondrial Biology
Background:
- Missense mutations in valosin-containing protein (VCP) are linked to inclusion body myopathy, Paget disease with frontotemporal dementia (IBMPFD) and other neurodegenerative disorders.
- The precise pathological mechanisms underlying IBMPFD remain unclear, and effective treatments are currently unavailable.
Purpose of the Study:
- To investigate the role of VCP in mitochondrial dynamics and explore potential therapeutic strategies for IBMPFD.
- To establish and utilize an in vivo Drosophila model of IBMPFD to study disease pathology and test therapeutic interventions.
Main Methods:
- Utilized an adult Drosophila muscle model to recapitulate IBMPFD pathologies.
- Investigated the interaction between VCP and Mitofusin, a key regulator of mitochondrial outer membrane fusion.
- Assessed the efficacy of VCP inhibitors in Drosophila models and patient-derived fibroblasts.
Main Results:
- Endogenous VCP negatively regulates Mitofusin, essential for mitochondrial fusion.
- Common VCP disease mutants function as hyperactive alleles, disrupting Mitofusin regulation.
- VCP inhibitors effectively suppressed mitochondrial defects, muscle damage, and cell death in Drosophila models.
- Inhibitors also ameliorated mitochondrial fusion and respiratory deficits in IBMPFD patient fibroblasts.
Conclusions:
- VCP disease mutants likely cause IBMPFD through a gain-of-function mechanism.
- VCP inhibitors demonstrate significant therapeutic potential for treating IBMPFD and related mitochondrial disorders.
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