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.

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.

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

Substances

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

Supplementary concepts

  • Charcot-Marie-Tooth disease, dominant intermediate 2