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J Biol Chem. 2017 May 26;292(21):8907-8917. doi: 10.1074/jbc.M116.762898. Epub 2017 Mar 30.

Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons.

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From the Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
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.
the Institute of Neurology, MRC Centre for Neuromuscular Diseases, London WC1N 3BG, United Kingdom.
the Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, United Kingdom, and.
From the Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom,


Mutations in the gene encoding valosin-containing protein (VCP) lead to multisystem proteinopathies including frontotemporal dementia. We have previously shown that patient-derived VCP mutant fibroblasts exhibit lower mitochondrial membrane potential, uncoupled respiration, and reduced ATP levels. This study addresses the underlying basis for mitochondrial uncoupling using VCP knockdown neuroblastoma cell lines, induced pluripotent stem cells (iPSCs), and iPSC-derived cortical neurons from patients with pathogenic mutations in VCP Using fluorescent live cell imaging and respiration analysis we demonstrate a VCP mutation/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.


ADP; ANT; ATP; VCP; amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); induced pluripotent stem cell (iPS cell) (iPSC); mitochondria

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