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

Ludtmann, M H R; Arber, C; Bartolome, F; De Vicente, M; Preza, E; Carro, E; Houlden, H; Gandhi, S; Wray, S; Abramov, A Y

Authors

M H R Ludtmann

C Arber

F Bartolome

M De Vicente

E Preza

E Carro

H Houlden

S Gandhi

S Wray

A Y Abramov



Abstract

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.

Citation

Ludtmann, M. H. R., Arber, C., Bartolome, F., De Vicente, M., Preza, E., Carro, E., …Abramov, A. Y. (2017). Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons. Journal of Biological Chemistry, 292(21), 8907-8917. https://doi.org/10.1074/jbc.M116.762898

Journal Article Type Article
Acceptance Date Apr 1, 2017
Publication Date May 26, 2017
Deposit Date Jul 24, 2018
Publicly Available Date Jul 24, 2018
Journal JOURNAL OF BIOLOGICAL CHEMISTRY
Print ISSN 0021-9258
Electronic ISSN 1083-351X
Publisher American Society for Biochemistry and Molecular Biology
Peer Reviewed Peer Reviewed
Volume 292
Issue 21
Pages 8907-8917
DOI https://doi.org/10.1074/jbc.M116.762898
Public URL https://rvc-repository.worktribe.com/output/1391765

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