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

Abstract

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
Volume50
Issue number3
DOIs
StatePublished - Aug 5 2019

Keywords

  • 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

Fingerprint Dive into the research topics of 'Lysosomal Regulation of Inter-mitochondrial Contact Fate and Motility in Charcot-Marie-Tooth Type 2'. Together they form a unique fingerprint.

Cite this