Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels

Neuron. 2013 Apr 10;78(1):57-64. doi: 10.1016/j.neuron.2013.02.028. Epub 2013 Mar 14.

Abstract

Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%-2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / deficiency
  • Adenosine Triphosphatases / genetics*
  • Adenosine Triphosphate / metabolism*
  • Adult
  • Aged
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Case-Control Studies
  • Cell Cycle Proteins / deficiency
  • Cell Cycle Proteins / genetics*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Family Health
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology
  • Humans
  • Lipid Peroxidation / genetics
  • Luminescent Proteins / genetics
  • Magnesium / metabolism
  • Male
  • Membrane Potential, Mitochondrial / genetics
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Muscular Dystrophies, Limb-Girdle / genetics
  • Muscular Dystrophies, Limb-Girdle / metabolism
  • Muscular Dystrophies, Limb-Girdle / pathology
  • Mutation / genetics*
  • Myositis, Inclusion Body / genetics
  • Myositis, Inclusion Body / metabolism
  • Myositis, Inclusion Body / pathology
  • NAD / metabolism
  • Neuroblastoma / pathology
  • Neurons / ultrastructure*
  • Osteitis Deformans / genetics
  • Osteitis Deformans / metabolism
  • Osteitis Deformans / pathology
  • Oxygen Consumption / genetics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Transfection
  • Valosin Containing Protein

Substances

  • Cell Cycle Proteins
  • Luminescent Proteins
  • RNA, Small Interfering
  • NAD
  • Adenosine Triphosphate
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein
  • Vcp protein, mouse
  • Magnesium

Supplementary concepts

  • Inclusion Body Myopathy With Early-Onset Paget Disease And Frontotemporal Dementia