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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
PubMed

Insights

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.
Keywords:
ADPANTATPVCPamyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)induced pluripotent stem cell (iPS cell) (iPSC)mitochondria

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