Journal Article

A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore

Princen, Katrien, Vanderhaeghe, Silke, Van Damme, Philip, Goethals, Elien, Van Den Bosch, Ludo, Prerad, Jovan, Debroux, Eveline, Griffioen, Gerard, Tharkeshwar, Arun Kumar, Scheveneels, Wendy, Vints, Katlijn, Beckers, Jimmy, Fivaz, Marc

2024

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Adenosine triphosphatase / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Biomedical and Life Sciences / Biomedicine / Calcium - metabolism / Cell Line, Tumor / Dementia / Development and progression / Electron transport / Ethylenediaminetetraacetic acid / Frontotemporal dementia / Frontotemporal Dementia - genetics / Frontotemporal Dementia - metabolism / Frontotemporal Dementia - pathology / Genes / Genetic aspects / Humans / International economic relations / Membrane Potential, Mitochondrial - genetics / Mitochondria / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial dysfunction / Mitochondrial Membrane Transport Proteins - genetics / Mitochondrial Membrane Transport Proteins - metabolism / Mitochondrial permeability transition pore / Mitochondrial Permeability Transition Pore - metabolism / Mutation / Neurology / Neurosciences / Pathology / Permeability / Scientific equipment and supplies industry / Valosin Containing Protein - genetics / Valosin Containing Protein - metabolism / VCP