University of Oulu

EMBO Mol Med (2019) 11: e10488

CoA-dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases

Saved in:
Author: Lambrechts, Roald A.1; Schepers, Hein1; Yu, Yi1;
Organizations: 1Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
4Neurology Department, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
5Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.6 MB)
Persistent link:
Language: English
Published: EMBO Press, 2019
Publish Date: 2020-04-01


PKAN, CoPAN, MePAN, and PDH‐E2 deficiency share key phenotypic features but harbor defects in distinct metabolic processes. Selective damage to the globus pallidus occurs in these genetic neurodegenerative diseases, which arise from defects in CoA biosynthesis (PKAN, CoPAN), protein lipoylation (MePAN), and pyruvate dehydrogenase activity (PDH‐E2 deficiency). Overlap of their clinical features suggests a common molecular etiology, the identification of which is required to understand their pathophysiology and design treatment strategies. We provide evidence that CoA‐dependent activation of mitochondrial acyl carrier protein (mtACP) is a possible process linking these diseases through its effect on PDH activity. CoA is the source for the 4′‐phosphopantetheine moiety required for the posttranslational 4′‐phosphopantetheinylation needed to activate specific proteins. We show that impaired CoA homeostasis leads to decreased 4′‐phosphopantetheinylation of mtACP. This results in a decrease of the active form of mtACP, and in turn a decrease in lipoylation with reduced activity of lipoylated proteins, including PDH. Defects in the steps of a linked CoA‐mtACP‐PDH pathway cause similar phenotypic abnormalities. By chemically and genetically re‐activating PDH, these phenotypes can be rescued, suggesting possible treatment strategies for these diseases.

see all

Series: EMBO molecular medicine
ISSN: 1757-4676
ISSN-E: 1757-4684
ISSN-L: 1757-4676
Volume: 11
Issue: 12
Article number: e10488
DOI: 10.15252/emmm.201910488
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was supported by a VICI grant to O.S. (NWO‐grant 865.10.012). Part of the work has been performed at the UMCG Microscopy and Imaging Center (UMIC), which is sponsored by NWO‐grant 175‐010‐2009‐023. MAVL received a PhD stipendium from UMCG. The authors declare that they have no conflict of interest other than stated below. KJA is supported by grants from the Academy of Finland (267388) and the Sigrid Juselius Foundation.
Copyright information: © 2019 The Authors. Published under the terms of the CC BY 4.0 license.