Lysosomal Regulation of Inter-mitochondrial Contact Fate and Motility in Charcot-Marie-Tooth Type 2

Dev Cell. 2019 Aug 5;50(3):339-354.e4. doi: 10.1016/j.devcel.2019.05.033. Epub 2019 Jun 20.


Properly regulated mitochondrial networks are essential for cellular function and implicated in multiple diseases. Mitochondria undergo fission and fusion events, but the dynamics and regulation of a third event of inter-mitochondrial contact formation remain unclear. Using super-resolution imaging, we demonstrate that inter-mitochondrial contacts frequently form and play a fundamental role in mitochondrial networks by restricting mitochondrial motility. Inter-mitochondrial contact untethering events are marked and regulated by mitochondria-lysosome contacts, which are modulated by RAB7 GTP hydrolysis. Moreover, inter-mitochondrial contact formation and untethering are further regulated by Mfn1/2 and Drp1 GTP hydrolysis, respectively. Surprisingly, endoplasmic reticulum tubules are also present at inter-mitochondrial contact untethering events, in addition to mitochondrial fission and fusion events. Importantly, we find that multiple Charcot-Marie-Tooth type 2 disease-linked mutations in Mfn2 (CMT2A), RAB7 (CMT2B), and TRPV4 (CMT2C) converge on prolonged inter-mitochondrial contacts and defective mitochondrial motility, highlighting a role for inter-mitochondrial contacts in mitochondrial network regulation and disease.

Keywords: Charcot-Marie-Tooth type 2; Mfn2; RAB7; TRPV4; endoplasmic reticulum; inter-mitochondrial contact; lysosome; mitochondria; mitochondria-lysosome contact; super-resolution imaging.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / metabolism*
  • Endoplasmic Reticulum / metabolism
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab7 GTP-Binding Proteins


  • Mitochondrial Proteins
  • TRPV Cation Channels
  • TRPV4 protein, human
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • rab GTP-Binding Proteins

Supplementary concepts

  • Charcot-Marie-Tooth disease, dominant intermediate 2