title: Charcot-Marie-Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential.
abstract: Mutations in GDAP1 lead to recessively or dominantly inherited peripheral neuropathies (Charcot-Marie-Tooth disease, CMT), indicating that GDAP1 is essential for the viability of cells in the peripheral nervous system. GDAP1 contains domains characteristic of glutathione-S-transferases (GSTs), is located in the outer mitochondrial membrane and induces fragmentation of mitochondria. We found GDAP1 upregulated in neuronal HT22 cells selected for resistance against oxidative stress. GDAP1 over-expression protected against oxidative stress caused by depletion of the intracellular antioxidant glutathione (GHS) and against effectors of GHS depletion that affect the mitochondrial membrane integrity like truncated BH3-interacting domain death agonist and 12/15-lipoxygenase. Gdap1 knockdown, in contrast, increased the susceptibility of motor neuron-like NSC34 cells against GHS depletion. Over-expression of wild-type GDAP1, but not of GDAP1 with recessively inherited mutations that cause disease and reduce fission activity, increased the total cellular GHS content and the mitochondrial membrane potential up to a level where it apparently limits mitochondrial respiration, leading to reduced mitochondrial Ca(2+) uptake and superoxide production. Fibroblasts from autosomal-recessive CMT4A patients had reduced GDAP1 levels, reduced GHS concentration and a reduced mitochondrial membrane potential. Thus, our results suggest that the potential GST GDAP1 is implicated in the control of the cellular GHS content and mitochondrial activity, suggesting an involvement of oxidative stress in the pathogenesis of CMT4A.
authors.affiliation: Department of Neurology, University of Düsseldorf, D-40225 Düsseldorf, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Noack
authors.forename: Svenja
authors.initials: S
authors.lastname: Frede
authors.forename: Philipp
authors.initials: P
authors.lastname: Albrecht
authors.forename: Nadine
authors.initials: N
authors.lastname: Henke
authors.forename: Annika
authors.initials: A
authors.lastname: Pfeiffer
authors.forename: Katrin
authors.initials: K
authors.lastname: Knoll
authors.forename: Thomas
authors.initials: T
authors.lastname: Dehmel
authors.forename: Gerd
authors.initials: G
authors.lastname: Meyer Zu Hörste
authors.forename: Mark
authors.initials: M
authors.lastname: Stettner
authors.forename: Bernd C
authors.initials: BC
authors.lastname: Kieseier
authors.forename: Holger
authors.initials: H
authors.lastname: Summer
authors.forename: Stefan
authors.initials: S
authors.lastname: Golz
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kochanski
authors.forename: Martina
authors.initials: M
authors.lastname: Wiedau-Pazos
authors.forename: Susanne
authors.initials: S
authors.lastname: Arnold
authors.forename: Jan
authors.initials: J
authors.lastname: Lewerenz
authors.forename: Axel
authors.initials: A
authors.lastname: Methner
mesh_terms: D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: C118663:GDAP protein; D009419:Nerve Tissue Proteins; D005978:Glutathione