Bartolome, F;
Wu, HC;
Burchell, VS;
Preza, E;
Wray, S;
Mahoney, CJ;
Fox, NC;
... Plun-Favreau, H; + view all
(2013)
Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels.
Neuron
, 78
(1)
57 - 64.
10.1016/j.neuron.2013.02.028.
![[thumbnail of 1-s2.0-S0896627313001864-main.pdf]](https://discovery-pp.ucl.ac.uk/style/images/fileicons/application_pdf.png) Preview |
PDF
1-s2.0-S0896627313001864-main.pdf Download (859kB) |
Abstract
Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%-2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.
| Type: | Article |
|---|---|
| Title: | Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.neuron.2013.02.028 |
| Publisher version: | http://dx.doi.org/10.1016/j.neuron.2013.02.028 |
| Language: | English |
| Additional information: | © 2013 Elsevier Inc. This work is licensed under a Creative Commons Attribution 3.0 Unported License. PMCID: PMC3843114 |
| Keywords: | Adenosine Triphosphatases, Adenosine Triphosphate, Adult, Aged, Analysis of Variance, Animals, Animals, Newborn, Case-Control Studies, Cell Cycle Proteins, Cells, Cultured, Cerebral Cortex, Family Health, Female, Fibroblasts, Frontotemporal Dementia, Humans, Lipid Peroxidation, Luminescent Proteins, Magnesium, Male, Membrane Potential, Mitochondrial, Mice, Mice, Inbred C57BL, Middle Aged, Mitochondria, Muscular Dystrophies, Limb-Girdle, Mutation, Myositis, Inclusion Body, NAD, Neuroblastoma, Neurons, Osteitis Deformans, Oxygen Consumption, RNA, Small Interfering, Transfection |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1389865 |
Archive Staff Only
 |
View Item |
