title: Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission.
abstract: Mitochondria and peroxisomes can be fragmented by the process of fission. The fission machineries of both organelles share a set of proteins. GDAP1 is a tail-anchored protein of mitochondria and induces mitochondrial fragmentation. Mutations in GDAP1 lead to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy, and affect mitochondrial dynamics. Here, we show that GDAP1 is also targeted to peroxisomes mediated by the import receptor Pex19. Knockdown of GDAP1 leads to peroxisomal elongation that can be rescued by re-expressing GDAP1 and by missense mutated forms found in CMT patients. GDAP1-induced peroxisomal fission is dependent on the integrity of its hydrophobic domain 1, and on Drp1 and Mff, as is mitochondrial fission. Thus, GDAP1 regulates mitochondrial and peroxisomal fission by a similar mechanism. However, our results reveal also a more critical role of the amino-terminal GDAP1 domains, carrying most CMT-causing mutations, in the regulation of mitochondrial compared to peroxisomal fission.
authors.affiliation: Institute of Molecular Health Sciences, Cell Biology, Department of Biology, ETH Zurich, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
authors.forename: Nina
authors.initials: N
authors.lastname: Huber
authors.forename: Sofia
authors.initials: S
authors.lastname: Guimaraes
authors.forename: Michael
authors.initials: M
authors.lastname: Schrader
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Axel
authors.initials: A
authors.lastname: Niemann
mesh_terms: D000818:Animals; D019556:COS Cells; D048430:Cell Shape; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D002522:Chlorocebus aethiops; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D063154:Mitochondrial Dynamics; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D020675:Peroxisomes / Q000502:physiology*; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: C118663:GDAP protein; D008565:Membrane Proteins; C533267:Mff protein, human; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins