title: Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons.
abstract: Mutations in the gene encoding valosin-containing protein (VCP) lead to multisystem proteinopathies including frontotemporal dementia. We have previously shown that patient-derivedVCPmutant fibroblasts exhibit lower mitochondrial membrane potential, uncoupled respiration, and reduced ATP levels. This study addresses the underlying basis for mitochondrial uncoupling usingVCPknockdown neuroblastoma cell lines, induced pluripotent stem cells (iPSCs), and iPSC-derived cortical neurons from patients with pathogenic mutations inVCPUsing fluorescent live cell imaging and respiration analysis we demonstrate aVCPmutation/knockdown-induced dysregulation in the adenine nucleotide translocase, which results in a slower rate of ADP or ATP translocation across the mitochondrial membranes. This deregulation can explain the mitochondrial uncoupling and lower ATP levels in VCP mutation-bearing neurons via reduced ADP availability for ATP synthesis. This study provides evidence for a role of adenine nucleotide translocase in the mechanism underlying altered mitochondrial function in VCP-related degeneration, and this new insight may inform efforts to better understand and manage neurodegenerative disease and other proteinopathies.
authors.affiliation: From the Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors.forename: Marthe H R
authors.identifier: 0000-0003-1051-6425
authors.initials: MHR
authors.lastname: Ludtmann
authors.affiliation: From the Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Arber
authors.affiliation: the Neurodegenerative Disorders Group, Research Institute Hospital 12 de Octubre (i+12), Madrid 28041, Spain.|the Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), Madrid 28041, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bartolome
authors.affiliation: the Neurodegenerative Disorders Group, Research Institute Hospital 12 de Octubre (i+12), Madrid 28041, Spain.|the Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), Madrid 28041, Spain.
authors.forename: Macarena
authors.initials: M
authors.lastname: de Vicente
authors.affiliation: From the Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors.forename: Elisavet
authors.identifier: 0000-0003-4082-4621
authors.initials: E
authors.lastname: Preza
authors.affiliation: the Neurodegenerative Disorders Group, Research Institute Hospital 12 de Octubre (i+12), Madrid 28041, Spain.|the Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), Madrid 28041, Spain.
authors.forename: Eva
authors.identifier: 0000-0002-6504-4579
authors.initials: E
authors.lastname: Carro
authors.affiliation: the Institute of Neurology, MRC Centre for Neuromuscular Diseases, London WC1N 3BG, United Kingdom.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: the Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, United Kingdom, and.
authors.forename: Sonia
authors.identifier: 0000-0003-4395-2661
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: From the Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors.forename: Selina
authors.identifier: 0000-0003-3062-7050
authors.initials: S
authors.lastname: Wray
authors.affiliation: From the Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom, a.abramov@ucl.ac.uk.
authors.forename: Andrey Y
authors.identifier: 0000-0002-7646-7235
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D000244:Adenosine Diphosphate / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D001693:Biological Transport, Active / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: ADP; ANT; ATP; VCP; amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); induced pluripotent stem cell (iPS cell) (iPSC); mitochondria