Model of mitochondrial and lysosomal network regulation via coupled Mid51/Fis1 oligomerization complex. (A) Model—Normal: (1 and 2) Mid51 and Fis1 undergo coupled oligomerization in a Mid51/Fis1 complex on the outer mitochondrial membrane; (3 and 4) Mid51 oligomers promote Drp1 oligomerization and subsequent Drp1 GTP hydrolysis via Mff (red arrow), while Fis1 oligomers promote TBC1D15 (Rab7-GAP) recruitment to mitochondria to drive Rab7 GTP hydrolysis at mitochondria–lysosome tethers (green arrow). Inhibiting either Mid51/Fis1 oligomerization (Fis1(LA)), Rab7 GTP hydrolysis (TBC1D15(D397A)), or Drp1 GTP hydrolysis (Drp1(K38A); Mid51) disrupts this pathway (grey arrows). See Discussion for details. (B) Rab7 GTP hydrolysis promotes mitochondria–lysosome and inter-lysosomal contact untethering, while Drp1 GTP hydrolysis promotes mitochondrial fission and inter-mitochondrial untethering, resulting in untethering events which help redistribute both mitochondrial and lysosomal networks. (C) Model—Mid51 mutants); left: Mid51(Y240N) Drp1-binding domain mutant which is linked to dominant optic atrophy disrupts Drp1 recruitment but not Mid51 oligomerization, leading to the selective inhibition of Drp1 GTP hydrolysis; right: Mid51(R169W) oligomerization domain mutant which is potentially linked to Parkinson’s disease disrupts Mid51 oligomerization but not Drp1 recruitment, leading to uncoupled and defective Fis1 oligomerization and the selective inhibition of Rab7 GTP hydrolysis, resulting in the misregulation of lysosomal tethering dynamics.