1. A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore
- Author
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Silke Vanderhaeghe, Jovan Prerad, Arun Kumar Tharkeshwar, Elien Goethals, Katlijn Vints, Jimmy Beckers, Wendy Scheveneels, Eveline Debroux, Katrien Princen, Philip Van Damme, Marc Fivaz, Gerard Griffioen, and Ludo Van Den Bosch
- Subjects
Amyotrophic lateral sclerosis ,Frontotemporal dementia ,VCP ,Mitochondria ,Mitochondrial dysfunction ,Mitochondrial permeability transition pore ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA+ 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 R191Q/wt 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.
- Published
- 2024
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