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Published on: January 7, 2019
Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and
Marthe H R Ludtmann1, Charles Arber1, Fernando Bartolome2,3
1From the Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
The Journal of Biological Chemistry
|April 1, 2017
Summary
Valosin-containing protein (VCP) mutations impair mitochondrial function by disrupting adenine nucleotide translocase. This leads to reduced ATP production, explaining neurodegeneration in VCP-related proteinopathies.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mutations in valosin-containing protein (VCP) cause multisystem proteinopathies, including frontotemporal dementia.
- Previous studies linked VCP mutations to mitochondrial dysfunction, characterized by reduced membrane potential, uncoupled respiration, and lower ATP levels.
Purpose of the Study:
- To investigate the molecular basis of mitochondrial uncoupling in VCP-related neurodegeneration.
- To elucidate the role of adenine nucleotide translocase (ANT) in VCP mutation-associated mitochondrial dysfunction.
Main Methods:
- Utilized VCP knockdown neuroblastoma cell lines, induced pluripotent stem cells (iPSCs), and iPSC-derived cortical neurons from patients with VCP mutations.
- Employed fluorescent live cell imaging and respiration analysis to assess mitochondrial function and ANT activity.
Main Results:
- Demonstrated VCP mutation/knockdown-induced dysregulation of adenine nucleotide translocase (ANT).
- Observed a slower rate of ADP/ATP translocation across mitochondrial membranes in VCP-mutant cells.
- Linked reduced ADP availability for ATP synthesis to mitochondrial uncoupling and lower ATP levels.
Conclusions:
- Identified adenine nucleotide translocase (ANT) dysregulation as a key mechanism in VCP-related mitochondrial dysfunction.
- Provided evidence for ANT's role in the pathogenesis of VCP-associated neurodegeneration and proteinopathies.
- This insight may aid in understanding and managing VCP-related neurodegenerative diseases.
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