title: Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels.
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.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bartolome
authors.forename: Hsiu-Chuan
authors.initials: HC
authors.lastname: Wu
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Burchell
authors.forename: Elisavet
authors.initials: E
authors.lastname: Preza
authors.forename: Selina
authors.initials: S
authors.lastname: Wray
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Mahoney
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.forename: Antonio
authors.initials: A
authors.lastname: Canosa
authors.forename: Cristina
authors.initials: C
authors.lastname: Moglia
authors.forename: Jessica
authors.initials: J
authors.lastname: Mandrioli
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Richard W
authors.initials: RW
authors.lastname: Orrell
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.forename: Helene
authors.initials: H
authors.lastname: Plun-Favreau
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D008274:Magnesium / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000648:ultrastructure*; D010001:Osteitis Deformans / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D008164:Luminescent Proteins; D034741:RNA, Small Interfering; D009243:NAD; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; D008274:Magnesium