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Updated: Jan 17, 2026

Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons
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Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death

Mariana Joaquim1,2,3, Maria-Bianca Bulimaga1,2,3,4, Marie A Mohn1,2

  • 1Institute for Genetics, University of Cologne, 50674 Cologne, Germany.

Journal of Cell Science
|September 25, 2025
PubMed

Insights

Charcot-Marie-Tooth type 2A (CMT2A) involves variants in mitofusin 2 (MFN2). Research shows these variants increase endoplasmic reticulum stress and intrinsic apoptosis, suggesting cell death as a therapeutic target for CMT2A.

Area of Science:

  • Mitochondrial biology
  • Neurodegenerative diseases
  • Cellular stress responses

Background:

  • Charcot-Marie-Tooth (CMT) is an incurable neuropathy with limited genotype-phenotype correlation.
  • Mitofusin 2 (MFN2) variants cause CMT type 2A (CMT2A), a subtype affecting mitochondrial fusion.
  • MFN2 has roles beyond membrane dynamics, suggesting broader disease involvement.

Purpose of the Study:

  • To investigate the association between MFN2 variants and cellular dysfunction in CMT2A.
  • To explore the impact of CMT2A-associated MFN2 variants on cellular processes.
  • To identify potential therapeutic targets for CMT2A.

Main Methods:

  • Utilized human cellular models expressing CMT2A-associated MFN2 variants.
  • Assessed endoplasmic reticulum (ER) stress and apoptotic cell death markers.
  • Analyzed caspase cleavage, PARP1 cleavage, and BAX translocation to mitochondria.

Main Results:

  • Cells with CMT2A MFN2 variants exhibited increased ER stress and apoptotic cell death.
  • Evidence pointed to intrinsic apoptosis pathway activation, including caspase cascade and BAX translocation.
  • Disruption of mitochondrial dynamics alone did not correlate with cell death, but MFN1/MFN2 expression reduced apoptosis markers.

Conclusions:

  • Excessive intrinsic apoptosis is a key feature of CMT2A.
  • MFN2 variants in CMT2A contribute to cellular dysfunction via ER stress and apoptosis.
  • Targeting intrinsic apoptosis pathways may offer a therapeutic strategy for CMT2A.
Keywords:
ApoptosisCMT2ACell deathCharcot–Marie–ToothFusionMFN2Mitochondria

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