GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance.
Mutations in the GDAP1 gene lead to recessively or dominantly inherited peripheral neuropathies (Charcot-Marie-Tooth disease; CMT). Here, we demonstrate that GDAP1 is a mitochondrial fission factor whose activity is dependent on the fission factors Drp1 and Fis1. Unlike other mitochondrial fission factors, GDAP1 overexpression or knockdown does not influence the susceptibility of cells to apoptotic stimuli. Recessively inherited CMT-associated forms of GDAP1 (rmGDAP1s) have reduced fission activity, whereas dominantly inherited forms (dmGDAP1s) interfere with mitochondrial fusion. Only the expression of dmGDAP1s increases the production of ROS, leads to uneven mitochondrial transmembrane potentials, and enhances the susceptibility to apoptotic stimuli. Taken together, our results indicate that wild-type GDAP1 promotes fission without increasing the risk of apoptosis. In CMT, recessive GDAP1 mutations are associated with reduced fission activity, while dominant mutations impair mitochondrial fusion and cause mitochondrial damage. Thus, different cellular mechanisms that disturb mitochondrial dynamics underlie the similar clinical manifestations caused by GDAP1 mutations, depending on the mode of inheritance.
Niemann
Axel
A
Institute of Cell Biology, Department of Biology, ETH Zürich, Switzerland. axel.niemann@cell.biol.ethz.ch
Wagner
Konstanze Marion
KM
Ruegg
Marcel
M
Suter
Ueli
U
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D055029:Inverted Repeat Sequences; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D012313:RNA / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014741:Video Recording
C476525:FIS1 protein, human; C118663:GDAP protein; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D012313:RNA