TY - JOUR
T1 - CoA-dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases
AU - Lambrechts, Roald A.
AU - Schepers, Hein
AU - Yu, Yi
AU - van der Zwaag, Marianne
AU - Autio, Kaija J.
AU - Vieira-Lara, Marcel A.
AU - Bakker, Barbara M.
AU - Tijssen, Marina A.
AU - Hayflick, Susan J.
AU - Grzeschik, Nicola A.
AU - Sibon, Ody C.M.
N1 - Publisher Copyright:
© 2019 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - 4′-phosphopantetheinylation
KW - Coenzyme A
KW - NBIA
KW - NDUFAB1
KW - mtACP
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U2 - 10.15252/emmm.201910488
DO - 10.15252/emmm.201910488
M3 - Article
C2 - 31701655
AN - SCOPUS:85074734115
SN - 1757-4676
VL - 11
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
M1 - e10488
ER -