ACP Acylation Is an Acetyl-CoA-Dependent Modification Required for Electron Transport Chain Assembly

Vranken, Jonathan G. Van; Nowinski, Sara M.; Clowers, Katie J.; Jeong, Mi Young; Ouyang, Yeyun; Berg, Jordan A.; Gygi, Jeremy P.; Gygi, Steven P.; Winge, Dennis R.; Rutter, Jared

doi:10.1016/j.molcel.2018.06.039

Cited by 87 publications

(142 citation statements)

References 49 publications

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“…These activated proteins play essential roles in mammals, including as acyl carrier proteins (Praphanphoj et al , ; Donato et al , ). Mitochondrial acyl carrier protein (mtACP), which requires phosphopantetheinyl activation, is essential for electron transport, type II fatty acid synthesis, iron–sulfur cluster biogenesis, and tRNA processing via RNase P (Chuman & Brody, ; Brody et al , ; Autio et al , ; Hiltunen et al , ; Van Vranken et al , , ). Moreover, mtACP is a key factor in coordinating the cellular response to nutrient availability with intermediary metabolism via its requirement for acetyl‐CoA (Hiltunen et al , ; Kursu et al , ; Van Vranken et al , ).…”

Section: Discussionmentioning

confidence: 99%

4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

et al. 2019

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Pantothenate kinase‐associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease‐vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4′‐phosphopantetheine, normalized levels of the CoA‐, iron‐, and dopamine‐related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4′‐phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron–sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4′‐phosphopantetheine as a candidate therapeutic for PKAN.

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Section: Discussionmentioning

confidence: 99%

4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

et al. 2019

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“…mtACP serves numerous functions that are conserved across species. Indeed, NDUFAB1, the human ortholog of mtACP, is a subunit of and required for the assembly of complex I (Vinothkumar et al, 2014;Van Vranken et al, 2018) and is involved in iron-sulfur biogenesis (Van Vranken et al, 2016). It is possible that the majority of the RNAi-induced phenotype in the Drosophila wing arises from reduced PDH activity and not from other affected processes downstream from holo-mtACP.…”

Section: Discussionmentioning

confidence: 99%

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

Lambrechts

Schepers

et al. 2019

EMBO Mol Med

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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.

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“…Type I animal FASs (including human FAS) terminate synthesis through the action of a thioesterase (TE), releasing the free acid as product. Type II systems in bacteria and mitochondria terminate synthesis through forwarding of acyl‐ACP to lipid biosynthetic pathways, as well as lipoic acid synthesis and electron transport chain (ETC) complex assembly . Type II synthesis in plants is terminated by TE‐mediated hydrolysis…”

Section: Basic Principles Of Fatty Acid Biosynthesismentioning

confidence: 99%

“…Whereas the short‐chain C 8 fatty acids are the precursors of lipoic acid synthesis, the fate of long fatty acids produced in mitochondria is only poorly understood . Recently, it was shown that mitochondrial ACPs carrying long acyl chains are accessory subunits of the ETC complex I …”

Section: The Structure Of Type II Fassmentioning

confidence: 99%

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Fatty Acid Biosynthesis: Chain‐Length Regulation and Control

et al. 2019

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De novo biosynthesis of fatty acids is an iterative process requiring strict regulation of the lengths of the produced fatty acids. In this review, we focus on the factors determining chain lengths in fatty acid biosynthesis. In a nutshell, the process of chain‐length regulation can be understood as the output of a chain‐elongating C−C bond forming reaction competing with a terminating fatty acid release function. At the end of each cycle in the iterative process, the synthesizing enzymes need to “decide” whether the growing chain is to be elongated through another cycle or released as the “mature” fatty acid. Recent research has shed light on the factors determining fatty acid chain length and has also achieved control over chain length for the production of the technologically interesting short‐chain (C4–C8) and medium‐chain (C10–C14) fatty acids.

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ACP Acylation Is an Acetyl-CoA-Dependent Modification Required for Electron Transport Chain Assembly

Cited by 87 publications

References 49 publications

4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

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

Fatty Acid Biosynthesis: Chain‐Length Regulation and Control

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