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.

Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels.

CALVO, Andrea;A. Canosa;MOGLIA, Cristina;CHIO', Adriano;
2013-01-01

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.
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http://dx.doi.org/10.1016/j.neuron.2013.02.028
Adenosine Triphosphatases; deficiency/genetics, Adenosine Triphosphate; metabolism, Adult, Aged, Analysis of Variance, Animals, Animals; Newborn, Case-Control Studies, Cell Cycle Proteins; deficiency/genetics, Cells; Cultured, Cerebral Cortex; cytology, Family Health, Female, Fibroblasts; metabolism/pathology, Frontotemporal Dementia; genetics/metabolism/pathology, Humans, Lipid Peroxidation; genetics, Luminescent Proteins; genetics, Magnesium; metabolism, Male, Membrane Potential; Mitochondrial; genetics, Mice, Mice; Inbred C57BL, Middle Aged, Mitochondria; genetics/metabolism/pathology, Muscular Dystrophies; Limb-Girdle; genetics/metabolism/pathology, Mutation; genetics, Myositis; Inclusion Body; genetics/metabolism/pathology, NAD; metabolism, Neuroblastoma; pathology, Neurons; ultrastructure, Osteitis Deformans; genetics/metabolism/pathology, Oxygen Consumption; genetics, RNA; Small Interfering; genetics/metabolism, Transfection
F. Bartolome;H. Wu;V. S. Burchell;E. Preza;S. Wray;C. J. Mahoney;N. C. Fox;A. Calvo;A. Canosa;C. Moglia;J. Mandrioli;A. Chiò;R. W. Orrell;H. Houlden;J. Hardy;A. Y. Abramov;H. Plun-Favreau
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/135582
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