Journal
NEURON
Volume 78, Issue 1, Pages 57-64Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2013.02.028
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Funding
- Spanish Ministerio de Educacion through FECYT
- MRC [G0700183]
- ALS Association Initiated award [2109]
- Motor Neuron Disease Association
- Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- European Community [259867, 278611]
- Motor Neuron Disease Association [6040]
- MRC [G1001253, G108/638, G0701075, MR/K000608/1, MC_G1000735, G0700183, G0802760, MR/J004758/1] Funding Source: UKRI
- Medical Research Council [G1001253, G0701075, MC_G1000735, G0802760, G0700183, MR/K000608/1, G108/638, MR/J004758/1] Funding Source: researchfish
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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.
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