Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics

J Cell Biol. 2022 Oct 3;221(10):e202206140. doi: 10.1083/jcb.202206140. Epub 2022 Sep 1.


Lysosomes are highly dynamic organelles implicated in multiple diseases. Using live super-resolution microscopy, we found that lysosomal tethering events rarely undergo lysosomal fusion, but rather untether over time to reorganize the lysosomal network. Inter-lysosomal untethering events are driven by a mitochondrial Mid51/Fis1 complex that undergoes coupled oligomerization on the outer mitochondrial membrane. Importantly, Fis1 oligomerization mediates TBC1D15 (Rab7-GAP) mitochondrial recruitment to drive inter-lysosomal untethering via Rab7 GTP hydrolysis. Moreover, inhibiting Fis1 oligomerization by either mutant Fis1 or a Mid51 oligomerization mutant potentially associated with Parkinson's disease prevents lysosomal untethering events, resulting in misregulated lysosomal network dynamics. In contrast, dominant optic atrophy-linked mutant Mid51, which does not inhibit Mid51/Fis1 coupled oligomerization, does not disrupt downstream lysosomal dynamics. As Fis1 conversely also regulates Mid51 oligomerization, our work further highlights an oligomeric Mid51/Fis1 mitochondrial complex that mechanistically couples together both Drp1 and Rab7 GTP hydrolysis machinery at mitochondria-lysosome contact sites. These findings have significant implications for organelle networks in cellular homeostasis and human disease.

Publication types

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

MeSH terms

  • Dynamins / metabolism
  • GTPase-Activating Proteins / metabolism
  • Guanosine Triphosphate / metabolism
  • Humans
  • Lysosomes* / genetics
  • Lysosomes* / metabolism
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Mitochondria / genetics
  • Mitochondrial Dynamics*
  • Mitochondrial Proteins* / genetics
  • Mitochondrial Proteins* / metabolism
  • Peptide Elongation Factors* / genetics
  • Peptide Elongation Factors* / metabolism
  • rab7 GTP-Binding Proteins / metabolism


  • FIS1 protein, human
  • GTPase-Activating Proteins
  • MIEF1 protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • Peptide Elongation Factors
  • TBC1D15 protein, human
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • Guanosine Triphosphate
  • DNM1L protein, human
  • Dynamins