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

Christina Wolf, Alireza Pouya, Sara Bitar, Annika Pfeiffer, Diones Bueno, Liliana Rojas-Charry, Sabine Arndt, David Gomez-Zepeda, Stefan Tenzer, Federica Dal Bello, Caterina Vianello, Sandra Ritz, Jonas Schwirz, Kristina Dobrindt, Michael Peitz, Eva Maria Hanschmann, Pauline Mencke, Ibrahim Boussaad, Marion Silies, Oliver BrüstleMarta Giacomello, Rejko Krüger, Axel Methner*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

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 and beta-tubulin 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. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.

Original languageEnglish
Article number541
JournalCommunications Biology
Volume5
Issue number1
DOIs
Publication statusPublished - 3 Jun 2022

Keywords

  • Actin Cytoskeleton/metabolism
  • Actins/metabolism
  • Humans
  • Mitochondria/metabolism
  • Nerve Tissue Proteins/metabolism
  • Neuroblastoma/metabolism
  • Pyruvate Dehydrogenase Complex/metabolism

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