TY - JOUR
T1 - GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton
AU - Wolf, Christina
AU - Pouya, Alireza
AU - Bitar, Sara
AU - Pfeiffer, Annika
AU - Bueno, Diones
AU - Rojas-Charry, Liliana
AU - Arndt, Sabine
AU - Gomez-Zepeda, David
AU - Tenzer, Stefan
AU - Bello, Federica Dal
AU - Vianello, Caterina
AU - Ritz, Sandra
AU - Schwirz, Jonas
AU - Dobrindt, Kristina
AU - Peitz, Michael
AU - Hanschmann, Eva Maria
AU - Mencke, Pauline
AU - Boussaad, Ibrahim
AU - Silies, Marion
AU - Brüstle, Oliver
AU - Giacomello, Marta
AU - Krüger, Rejko
AU - Methner, Axel
N1 - Funding Information:
The excellent support by the IMB Core Facility Microscopy is gratefully acknowledged. This work was supported by grants of the Deutsche Forschungsgemeinschaft to A.M. (CRC1080 project A10) and to A.M. and E.M.H. and S.T. (DFG ME1922 16-1; Ha 8334/2-2; TE599/6-1) within the priority program 1710. This work was supported by an Excellence Grant of the Luxembourg National Research Fund (FNR) within the PEARL program (FNR; FNR/P13/6682797 to R.K.). Work of R.K. is further supported by a grant from the FNR within the National Centre of Excellence in Research on Parkinson’s disease (NCER-PD). We thank the Disease Modelling and Screening Platform of the Luxembourg Institute of Systems Biomedicine and the Luxembourg Institute of Health for their support on high-content imaging of motoneurons. We thank Marion Silies for excellent and exhaustive proofreading.
Funding Information:
The excellent support by the IMB Core Facility Microscopy is gratefully acknowledged. This work was supported by grants of the Deutsche Forschungsgemeinschaft to A.M. (CRC1080 project A10) and to A.M. and E.M.H. and S.T. (DFG ME1922 16-1; Ha 8334/2-2; TE599/6-1) within the priority program 1710. This work was supported by an Excellence Grant of the Luxembourg National Research Fund (FNR) within the PEARL program (FNR; FNR/P13/6682797 to R.K.). Work of R.K. is further supported by a grant from the FNR within the National Centre of Excellence in Research on Parkinson’s disease (NCER-PD). We thank the Disease Modelling and Screening Platform of the Luxembourg Institute of Systems Biomedicine and the Luxembourg Institute of Health for their support on high-content imaging of motoneurons. We thank Marion Silies for excellent and exhaustive proofreading.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/3
Y1 - 2022/6/3
N2 - 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.
AB - 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.
KW - Actin Cytoskeleton/metabolism
KW - Actins/metabolism
KW - Humans
KW - Mitochondria/metabolism
KW - Nerve Tissue Proteins/metabolism
KW - Neuroblastoma/metabolism
KW - Pyruvate Dehydrogenase Complex/metabolism
UR - https://www.scopus.com/pages/publications/85131210698
UR - https://pubmed.ncbi.nlm.nih.gov/35662277
U2 - 10.1038/s42003-022-03487-6
DO - 10.1038/s42003-022-03487-6
M3 - Article
C2 - 35662277
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 541
ER -