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

Yvette C. Wong, Wesley Peng, Dimitri Krainc*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)339-354.e4
JournalDevelopmental Cell
Issue number3
StatePublished - Aug 5 2019


  • Charcot-Marie-Tooth type 2
  • Mfn2
  • RAB7
  • TRPV4
  • endoplasmic reticulum
  • inter-mitochondrial contact
  • lysosome
  • mitochondria
  • mitochondria-lysosome contact
  • super-resolution imaging

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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