title: Pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation.
abstract: 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 (PDK3(R158H)) leads to the attenuation of PDC through hyper-phosphorylation of E1 at selected serine residues. This hyper-phosphorylation can be reversed by treating the PDK3(R158H) 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.
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: gonzalo.perez-siles@sydney.edu.au.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Perez-Siles
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ly
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Grant
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Drew
authors.affiliation: Department of Neurology, Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia; Neuroscience Research, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; Department of Pediatrics, The University of Melbourne, VIC, Australia.
authors.forename: Eppie M
authors.initials: EM
authors.lastname: Yiu
authors.affiliation: Department of Neurology, Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia; Neuroscience Research, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; Department of Pediatrics, The University of Melbourne, VIC, Australia.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Chuang
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Shih-Chia
authors.initials: SC
authors.lastname: Tso
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia; Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia; Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: marina.kennerson@sydney.edu.au.
authors.forename: Marina L
authors.initials: ML
authors.lastname: Kennerson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D007527:Isoenzymes; C000631431:PDK3 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases
keywords: Dichloroacetic acid; Mitochondria; Patient fibroblasts; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase 3; X-linked Charcot-Marie-Tooth neuropathy