Selective mitochondrial depletion, apoptosis resistance, and increased mitophagy in human Charcot-Marie-Tooth 2A motor neurons

Hum Mol Genet. 2016 Oct 1;25(19):4266-4281. doi: 10.1093/hmg/ddw258. Epub 2016 Aug 9.


Charcot-Marie-Tooth 2A (CMT2A) is an inherited peripheral neuropathy caused by mutations in MFN2, which encodes a mitochondrial membrane protein involved in mitochondrial network homeostasis. Because MFN2 is expressed ubiquitously, the reason for selective motor neuron (MN) involvement in CMT2A is unclear. To address this question, we generated MNs from induced pluripotent stem cells (iPSCs) obtained from the patients with CMT2A as an in vitro disease model. CMT2A iPSC-derived MNs (CMT2A-MNs) exhibited a global reduction in mitochondrial content and altered mitochondrial positioning without significant differences in survival and axon elongation. RNA sequencing profiles and protein studies of key components of the apoptotic executioner program (i.e. p53, BAX, caspase 8, cleaved caspase 3, and the anti-apoptotic marker Bcl2) demonstrated that CMT2A-MNs are more resistant to apoptosis than wild-type MNs. Exploring the balance between mitochondrial biogenesis and the regulation of autophagy-lysosome transcription, we observed an increased autophagic flux in CMT2A-MNs that was associated with increased expression of PINK1, PARK2, BNIP3, and a splice variant of BECN1 that was recently demonstrated to be a trigger for mitochondrial autophagic removal. Taken together, these data suggest that the striking reduction in mitochondria in MNs expressing mutant MFN2 is not the result of impaired biogenesis, but more likely the consequence of enhanced mitophagy. Thus, these pathways represent possible novel molecular therapeutic targets for the development of an effective cure for this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Autophagy / genetics
  • Beclin-1 / genetics
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / metabolism
  • Charcot-Marie-Tooth Disease / pathology
  • GTP Phosphohydrolases / biosynthesis
  • GTP Phosphohydrolases / genetics*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Membrane Potential, Mitochondrial / genetics
  • Membrane Proteins / genetics
  • Mitochondrial Proteins / biosynthesis
  • Mitochondrial Proteins / genetics*
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Protein Kinases / genetics
  • Proto-Oncogene Proteins / genetics
  • Ubiquitin-Protein Ligases / genetics


  • BECN1 protein, human
  • BNIP3 protein, human
  • Beclin-1
  • Membrane Proteins
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • GTP Phosphohydrolases
  • MFN2 protein, human

Supplementary concepts

  • Charcot-Marie-Tooth Disease, Axonal, Type 2a1