Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons.
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.
['Ludtmann|Marthe H R|MHR|0000-0003-1051-6425', 'Arber|Charles|C|', 'Bartolome|Fernando|F|', 'de Vicente|Macarena|M|', 'Preza|Elisavet|E|0000-0003-4082-4621', 'Carro|Eva|E|0000-0002-6504-4579', 'Houlden|Henry|H|', 'Gandhi|Sonia|S|0000-0003-4395-2661', 'Wray|Selina|S|0000-0003-3062-7050', 'Abramov|Andrey Y|AY|0000-0002-7646-7235']
D000244:Adenosine Diphosphate D000251:Adenosine Triphosphatases D000255:Adenosine Triphosphate D001693:Biological Transport, Active D018797:Cell Cycle Proteins D045744:Cell Line, Tumor D006801:Humans D057026:Induced Pluripotent Stem Cells D000226:Mitochondrial ADP, ATP Translocases D051336:Mitochondrial Membranes D009154:Mutation D019636:Neurodegenerative Diseases D009474:Neurons D057165:Proteostasis Deficiencies D000074405:Valosin Containing Protein
VCP ADP ATP ANT amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease) induced pluripotent stem cell (iPS cell) (iPSC) mitochondria