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

Gonzalo Perez-Siles; Carolyn Ly; Adrienne Grant; Alexander P Drew; Eppie M Yiu; Monique M Ryan; David T Chuang; Shih-Chia Tso; Garth A Nicholson; Marina L Kennerson

doi:10.1016/j.nbd.2016.07.001

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

Neurobiol Dis. 2016 Oct:94:237-44. doi: 10.1016/j.nbd.2016.07.001. Epub 2016 Jul 5.

Authors

Affiliations

¹ 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.
² Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, NSW, Australia.
³ 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.
⁴ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ 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.
⁶ 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.

PMID: 27388934
DOI: 10.1016/j.nbd.2016.07.001

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.

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

MeSH terms

Adenosine Triphosphate / metabolism
Charcot-Marie-Tooth Disease / metabolism*
Humans
Isoenzymes / metabolism
Mitochondria / metabolism*
Mutation* / genetics
Phosphorylation
Protein Serine-Threonine Kinases / genetics*
Pyruvate Dehydrogenase Acetyl-Transferring Kinase

Substances

Isoenzymes
PDK3 protein, human
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Adenosine Triphosphate
Protein Serine-Threonine Kinases

Grants and funding

R01 DK062306/DK/NIDDK NIH HHS/United States