UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels.

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. Green open access

[img]
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 > Provost and Vice Provost Offices
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: http://discovery.ucl.ac.uk/id/eprint/1389865
Downloads since deposit
283Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item