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

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; Ludo Van Den Bosch

doi:10.1186/s40478-024-01866-0

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

Acta Neuropathol Commun. 2024 Oct 10;12(1):161. doi: 10.1186/s40478-024-01866-0.

Authors

Silke Vanderhaeghe^#^{1

2

3}, Jovan Prerad^#³, Arun Kumar Tharkeshwar^{4

5}, Elien Goethals^{1

3}, Katlijn Vints⁶, Jimmy Beckers^{1

2}, Wendy Scheveneels^{1

2}, Eveline Debroux³, Katrien Princen³, Philip Van Damme^{1

7}, Marc Fivaz⁸, Gerard Griffioen⁹, Ludo Van Den Bosch^{10

11}

Affiliations

¹ Laboratory of Neurobiology, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium.
² Laboratory of Neurobiology, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
³ reMYND, Leuven, Belgium.
⁴ Department of Human Genetics, KU Leuven - University of Leuven, Leuven, Belgium.
⁵ KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven - University of Leuven, Leuven, Belgium.
⁶ Electron Microscopy Platform and VIB-Bioimaging Core, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
⁷ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
⁸ reMYND, Leuven, Belgium. [email protected].
⁹ reMYND, Leuven, Belgium. [email protected].
¹⁰ Laboratory of Neurobiology, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium. [email protected].
¹¹ Laboratory of Neurobiology, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium. [email protected].

^# Contributed equally.

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.

Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Mitochondria; Mitochondrial dysfunction; Mitochondrial permeability transition pore; VCP.

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Amyotrophic Lateral Sclerosis* / pathology
Calcium / metabolism
Cell Line, Tumor
Frontotemporal Dementia* / genetics
Frontotemporal Dementia* / metabolism
Frontotemporal Dementia* / pathology
Humans
Membrane Potential, Mitochondrial / genetics
Mitochondria* / metabolism
Mitochondria* / pathology
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Permeability Transition Pore* / metabolism
Mutation*
Valosin Containing Protein* / genetics
Valosin Containing Protein* / metabolism

Substances

Valosin Containing Protein
Mitochondrial Permeability Transition Pore
VCP protein, human
Mitochondrial Membrane Transport Proteins
Calcium

Abstract

MeSH terms

Substances

Grants and funding