4AR, D2K, 2KR: GDAP1 mutations differ in their effects on mitochondrial dynamics

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(Note: GDAP mutations are found in Types 4A Recessive, Dominant 2K, Recessive

2K)

Neurobiol Dis. 2009 Sep 24.

GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis

depending on the mode of inheritance.

Niemann A, Wagner KM, Ruegg M, Suter U.

Institute of Cell Biology, Department of Biology, ETH Zurich, Switzerland.

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.