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GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton

ABSTRACT: Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. Changes in the actin cytoskeleton also disrupt mitochondria-ER contact sites. This results in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, these findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Neuroblastoma

SUBMITTER: David Gomez-Zepeda

LAB HEAD: Stefan Tenzer

PROVIDER: PXD028460 | Pride | 2022-08-12

REPOSITORIES: Pride

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GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.

Wolf Christina C Pouya Alireza A Bitar Sara S Pfeiffer Annika A Bueno Diones D Rojas-Charry Liliana L Arndt Sabine S Gomez-Zepeda David D Tenzer Stefan S Bello Federica Dal FD Vianello Caterina C Ritz Sandra S Schwirz Jonas J Dobrindt Kristina K Peitz Michael M Hanschmann Eva-Maria EM Mencke Pauline P Boussaad Ibrahim I Silies Marion M Brüstle Oliver O Giacomello Marta M Krüger Rejko R Methner Axel A

Communications biology 20220603 1

Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca<sup>2+</sup> homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine ...[more]

PMID: 35662277

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Project description:This a model from the article: Minimal model of beta-cell mitochondrial Ca2+ handling. Magnus G, Keizer J. Am J Physiol. 1997 Aug;273(2 Pt 1):C717-33. 9277370 , Abstract: We develop a simplified, but useful, mathematical model to describe Ca2+ handling by mitochondria in the pancreatic beta-cell. The model includes the following six transport mechanisms in the inner mitochondrial membrane: proton pumping via respiration and proton uptake by way of the F1Fzero-ATPase (adapted from D. Pietrobon and S. Caplan. Biochemistry 24: 5764-5778, 1985), a proton leak, adenine nucleotide exchange, the Ca2+ uniporter, and Na+/Ca2+ exchange. Each mechanism is developed separately into a kinetic model for the rate of transport, with parameters taken from experiments on isolated mitochondrial preparations. These mechanisms are combined in a modular fashion first to describe state 4 (nonphosphorylating) and state 3 (phosphorylating) mitochondria with mitochondrial NADH and Ca2+ concentrations as fixed parameters and then to describe Ca2+ handling with variable mitochondrial Ca2+ concentration. Simulations are compared to experimental measurements and agree well with the threshold for Ca2+ uptake, measured mitochondrial Ca2+ levels, and the influence of Ca2+ on oxygen uptake. In the absence of Ca2+ activation of mitochondrial dehydrogenases, the simulations predict a significant reduction in the rate of production of ATP that involves a "short circuit" via Ca2+ uptake through the uniporter. This effect suggests a potential role for mitochondrial Ca2+ handling in determining the ATP-ADP ratio in the pancreatic beta-cell. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Magnus and Keizer (1997) The original CellML model was created by: Catherine Lloyd c.lloyd@aukland.ac.nz The University of Auckland The Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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