A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore
Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA<sup>+</sup> ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP<sup>R191Q/wt</sup> mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.
Authors
- Silke Vanderhaeghe
- Katrien Princen (ORCID: https://orcid.org/0000-0002-7209-6422)
- Philip Van Damme (ORCID: https://orcid.org/0000-0002-4010-2357)
- Marc Fivaz (ORCID: https://orcid.org/0000-0003-1003-7934)
- Arun Kumar Tharkeshwar (ORCID: https://orcid.org/0000-0002-5529-9754)
- Jimmy Beckers
- Katlijn Vints (ORCID: https://orcid.org/0000-0002-2893-752X)
- Ludo Van Den Bosch (ORCID: https://orcid.org/0000-0003-0104-4067)
- Gerard Griffioen (ORCID: https://orcid.org/0000-0003-2492-6046)
- Wendy Scheveneels
- Jovan Prerad
- Eveline Debroux (ORCID: https://orcid.org/0009-0005-2718-5580)
- Elien Goethals
Institutions
- Allen Institute for Brain Science (US)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Teledyne Technologies (United States) (US)
- KU Leuven (BE)
Publication Details
- Journal
- Acta Neuropathologica Communications
- Published
- 2024-10-10
- DOI
- https://doi.org/10.1186/s40478-024-01866-0
- Citations
- 7
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 2.58
Funders
- ALS Association
- Muscular Dystrophy Association
- Association Belge contre les Maladies Neuro-Musculaires
- Agentschap Innoveren en Ondernemen
- Target ALS
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Vlaamse regering