Pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation

Neurobiology of Disease

Adrienne Grant¹  Garth A. Nicholson²  Shih-Chia Tso³  Carolyn Ly⁴  Marina L. Kennerson⁵  David T. Chuang⁵  Monique M. Ryan⁶  Alexander P. Drew⁶  Eppie M. Yiu⁶  Gonzalo Perez-Siles⁶ 

[1] Corresponding authors at: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia.;Department of Pediatrics, The University of Melbourne, VIC, Australia;Neuroscience Research, Murdoch Childrens Research Institute, Melbourne, VIC, Australia;Sydney Medical School, University of Sydney, Sydney, NSW, Australia;Department of Neurology, Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia;Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia;

关键词: X-linked Charcot-Marie-Tooth neuropathy;    Pyruvate dehydrogenase kinase 3;    Pyruvate dehydrogenase complex;    Mitochondria;    Patient fibroblasts;    Dichloroacetic acid;   

DOI  :  

来源: DOAJ

【 摘 要 】

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. An X-linked form of CMT (CMTX6) is caused by a missense mutation (R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. PDK3 is one of 4 isoenzymes that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation of its first catalytic component pyruvate dehydrogenase (designated as E1). Mitochondrial PDC catalyses the oxidative decarboxylation of pyruvate to acetyl CoA and links glycolysis to the energy-producing Krebs cycle. We have previously shown the R158H mutation confers PDK3 enzyme hyperactivity. In this study we demonstrate that the increased PDK3 activity in patient fibroblasts (PDK3R158H) leads to the attenuation of PDC through hyper-phosphorylation of E1 at selected serine residues. This hyper-phosphorylation can be reversed by treating the PDK3R158H fibroblasts with the PDK inhibitor dichloroacetate (DCA). In the patient cells, down-regulation of PDC leads to increased lactate, decreased ATP and alteration of the mitochondrial network. Our findings highlight the potential to develop specific drug targeting of the mutant PDK3 as a therapeutic approach to treating CMTX6.

【 授权许可】

Unknown