期刊
NEUROBIOLOGY OF DISEASE
卷 36, 期 3, 页码 509-520出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2009.09.011
关键词
Apoptosis; Charcot-Marie-Tooth; Mitochondria; Neurodegeneration; Peripheral nervous system; Apoptosis; Fusion; Fission; Ganglioside-induced differentiation associated protein 1; Mitochondrial dynamics
资金
- ETH Zilrich
- Swiss National Science Foundation
- National Center for Competence in Research (NCCR) Neural Plasticity and Repai
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. (C) 2009 Elsevier Inc. All rights reserved.
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