Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease

Int J Mol Sci. 2019 Jan 18;20(2):403. doi: 10.3390/ijms20020403.


The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause several forms of CMT neuropathy, but the pathogenic mechanisms involved remain unclear. GDAP1 is an outer mitochondrial membrane protein highly expressed in neurons. It has been proposed to play a role in different aspects of mitochondrial physiology, including mitochondrial dynamics, oxidative stress processes, and mitochondrial transport along the axons. Disruption of the mitochondrial network in a neuroblastoma model of GDAP1-related CMT has been shown to decrease Ca2+ entry through the store-operated calcium entry (SOCE), which caused a failure in stimulation of mitochondrial respiration. In this review, we summarize the different functions proposed for GDAP1 and focus on the consequences for Ca2+ homeostasis and mitochondrial energy production linked to CMT disease caused by different GDAP1 mutations.

Keywords: GDAP1; calcium regulated cell respiration; mitochondrial location; recessive mutations; store operated calcium entry.

Publication types

  • Review

MeSH terms

  • Animals
  • Biological Transport
  • Calcium / metabolism*
  • Charcot-Marie-Tooth Disease / etiology*
  • Charcot-Marie-Tooth Disease / metabolism*
  • Charcot-Marie-Tooth Disease / pathology
  • Disease Susceptibility
  • Gene Expression Regulation
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics*
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Protein Transport
  • Signal Transduction


  • GDAP protein
  • Nerve Tissue Proteins
  • Calcium