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

Wolf, C.; Pouya, A.; Bitar, S.; Pfeiffer, A.; Bueno, D.; Arndt, S.; Tenzer, S.; Ritz, S.; Schwirz, J.; Dobrindt, K.; Peitz, M.; Bruestle, O.; Dal Bello, F.; Vianello, C.; Giacomello, M.; Hanschmann, E.-M.; Boussaad, I.; Krueger, R.; Methner, A.

doi:10.1101/2021.03.04.433895

bioRxiv · 10.1101/2021.03.04.433895

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

Wolf, C.·Pouya, A.·Bitar, S.·Pfeiffer, A.·Bueno, D.·Arndt, S.·Tenzer, S.·Ritz, S.·Schwirz, J.·Dobrindt, K.·Peitz, M.·Bruestle, O.·Dal Bello, F.·Vianello, C.·Giacomello, M.·Hanschmann, E.-M.·Boussaad, I.·Krueger, R.·Methner, A.

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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 redoxdependent 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.

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Wolf, C., Pouya, A., Bitar, S., Pfeiffer, A., Bueno, D., Arndt, S., Tenzer, S., Ritz, S., Schwirz, J., Dobrindt, K., Peitz, M., Bruestle, O., Dal Bello, F., Vianello, C., Giacomello, M., Hanschmann, E.-M., Boussaad, I., Krueger, R., Methner, A.. 2021-03-05. GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton. https://doi.org/10.1101/2021.03.04.433895

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