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PMID:23498975

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Citation

Bartolome, F, Wu, HC, Burchell, VS, Preza, E, Wray, S, Mahoney, CJ, Fox, NC, Calvo, A, Canosa, A, Moglia, C, Mandrioli, J, Chiò, A, Orrell, RW, Houlden, H, Hardy, J, Abramov, AY and Plun-Favreau, H (2013) Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron 78:57-64

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.

Links

PubMed PMC3843114 Online version:10.1016/j.neuron.2013.02.028

Keywords

Adenosine Triphosphatases/deficiency; Adenosine Triphosphatases/genetics; Adenosine Triphosphate/metabolism; Adult; Aged; Analysis of Variance; Animals; Animals, Newborn; Case-Control Studies; Cell Cycle Proteins/deficiency; Cell Cycle Proteins/genetics; Cells, Cultured; Cerebral Cortex/cytology; Family Health; Female; Fibroblasts/metabolism; Fibroblasts/pathology; Frontotemporal Dementia/genetics; Frontotemporal Dementia/metabolism; Frontotemporal Dementia/pathology; Humans; Lipid Peroxidation/genetics; Luminescent Proteins/genetics; Magnesium/metabolism; Male; Membrane Potential, Mitochondrial/genetics; Mice; Mice, Inbred C57BL; Middle Aged; Mitochondria/genetics; Mitochondria/metabolism; Mitochondria/pathology; Muscular Dystrophies, Limb-Girdle/genetics; Muscular Dystrophies, Limb-Girdle/metabolism; Muscular Dystrophies, Limb-Girdle/pathology; Mutation/genetics; Myositis, Inclusion Body/genetics; Myositis, Inclusion Body/metabolism; Myositis, Inclusion Body/pathology; NAD/metabolism; Neuroblastoma/pathology; Neurons/ultrastructure; Osteitis Deformans/genetics; Osteitis Deformans/metabolism; Osteitis Deformans/pathology; Oxygen Consumption/genetics; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TERA

involved_in

GO:0006734: NADH metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(CHEBI:16908)

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:0072389: flavin adenine dinucleotide catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(CHEBI:24040)

Seeded From UniProt

complete

MOUSE:TERA

involved_in

GO:0010918: positive regulation of mitochondrial membrane potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000540)
  • occurs_in:(CL:0000127)

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:0010918: positive regulation of mitochondrial membrane potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:0006734: NADH metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_input:(CHEBI:16908)

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:0072389: flavin adenine dinucleotide catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_input:(CHEBI:24040)

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:1903715: regulation of aerobic respiration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:1903862: positive regulation of oxidative phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:2001171: positive regulation of ATP biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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