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 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.

• Authors: 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 Brüstle, Marta Giacomello, Rejko Krüger, Axel Methner
• Journal: Communications biology (Commun Biol) Vol. 5 Issue 1 Pg. 541 (06 03 2022) ISSN: 2399-3642 [Electronic] England
• PMID: 35662277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Actins
• GDAP protein
• Nerve Tissue Proteins
• Pyruvate Dehydrogenase Complex

Topics

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