MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Heimer, Gali; Kerätär, Juha M.; Riley, Lisa G.; Balasubramaniam, Shanti; Eyal, Eran; Pietikäinen, Laura P.; Hiltunen, J. Kalervo; Marek‐Yagel, Dina; Hamada, Jeffrey; Gregory, Allison; Rogers, Caleb; Hogarth, Penelope; Nance, Martha; Shalva, Nechama; Veber, Alvit; Tzadok, Michal; Nissenkorn, Andreea; Tonduti, Davide; Renaldo, Florence; Kraoua, Ichraf; Panteghini, Celeste; Valletta, Lorella; Garavaglia, Barbara; Cowley, Mark J.; Gayevskiy, Velimir; Roscioli, Tony; Silberstein, Jonathon M.; Hoffmann, Chen; Raas‐Rothschild, Annick; Tiranti, Valeria; Anikster, Yair; Christodoulou, John; Kastaniotis, Alexander J.; Ben‐Zeev, Bruria; Hayflick, Susan J.; Bamshad, Michael J.; Leal, Suzanne M.; Nickerson, Deborah A.; Anderson, Peter M.; Annable, Marcus; Blue, Elizabeth; Buckingham, Kati J.; Chin, Jennifer; Chong, Jessica X.; Cornejo, Rodolfo; Davis, Colleen; Frazar, Christopher; He, Zongxiao; Jarvik, Gail P.; Jimenez, Guillaume; Johanson, Eric; Kolar, Tom; Krauter, Stephanie; Luksic, Daniel; Marvin, Colby T.; McGee, Sean; McGoldrick, Daniel; Patterson, Karynne; Pérez, María Cristina; Phillips, Sam W.; Pijoan, Jessica; Robertson, Peggy D.; Santos‐Cortez, Regie Lyn P.; Shankar, Aditi; Slattery, Krystal; Shively, Kathryn M.; Siegel, Deborah L.; Smith, Joshua D.; Tackett, Monica; Wang, Gao; Wegener, Marc; Weiss, Jeffrey M.; Wernick, Riana I.; Wheeler, Marsha M.; Yi, Qing

doi:10.1016/j.ajhg.2016.09.021

Cited by 89 publications

(98 citation statements)

References 59 publications

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“…These results showing that boosting PDH activity can dampen the deleterious effects of impaired CoA biosynthesis and further establish the connection between CoA production and PDH activity. (Heimer et al, 2016). While these findings support our hypothesis, a key player in this pathway, mtACP has not been investigated in mammalian systems with impaired PANK2 activity.…”

Section: Downregulation Of Key Steps Of the Coa-pdh Pathway During Desupporting

confidence: 59%

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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Section: Downregulation Of Key Steps Of the Coa-pdh Pathway During Desupporting

confidence: 59%

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

Lambrechts

Schepers

et al. 2019

EMBO Mol Med

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“…The first cases of a novel neurodegenerative human disorder (MEPAN, mitochondrial enoyl-CoA reductase protein associated neurodegeneration) caused by recessive mutations in the MECR (mitochondrial enoyl-CoA/ACP reductase) protein of mtFAS have been reported recently (11).…”

Section: Introductionmentioning

confidence: 99%

A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3

Monteuuis¹,

Suomi²,

Kerätär

et al. 2017

Biochemical Journal

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Mitochondrial fatty acid synthesis (mtFAS) is a highly conserved pathway essential for mitochondrial biogenesis. The mtFAS process is required for mitochondrial respiratory chain assembly and function, synthesis of the lipoic acid cofactor indispensable for the function of several mitochondrial enzyme complexes and essential for embryonic development in mice. Mutations in human mtFAS have been reported to lead to neurodegenerative disease. The source of malonyl-CoA for mtFAS in mammals has remained unclear. We report the identification of a conserved vertebrate mitochondrial isoform of ACC1 expressed from an ACACA transcript splicing variant. A specific knockdown (KD) of the corresponding transcript in mouse cells, or CRISPR/Cas9-mediated inactivation of the putative mitochondrial targeting sequence in human cells, leads to decreased lipoylation and mitochondrial fragmentation. Simultaneous KD of ACSF3, encoding a mitochondrial malonyl-CoA synthetase previously implicated in the mtFAS process, resulted in almost complete ablation of protein lipoylation, indicating that these enzymes have a redundant function in mtFAS. The discovery of a mitochondrial isoform of ACC1 required for lipoic acid synthesis has intriguing consequences for our understanding of mitochondrial disorders, metabolic regulation of mitochondrial biogenesis and cancer.

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“…Deficiencies in either of these enzymes, as well as disruptions in mitochondrial FASII or iron sulfur biogenesis, result in diminished lipoylation of PDH and OGDH and ultimately impaired mitochondrial function (30,33,34). The lipoyltransferase ortholog in mammals is LIPT1 and similar to Lip3 in S.cerevisiae, it lacks the ability to generate an activated lipoyl-AMP and therefore is thought to be downstream of LIPT2 (9,30,35).…”

Section: Lipoic Acid Synthesismentioning

confidence: 99%

Lipoic acid metabolism and mitochondrial redox regulation

Solmonson

DeBerardinis

2018

Journal of Biological Chemistry

330

255

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Lipoic acid is an essential cofactor for mitochondrial metabolism and is synthesized de novo using intermediates from mitochondrial fatty acid synthesis type II, S-adenosylmethionine and iron-sulfur clusters. This cofactor is required for catalysis by multiple mitochondrial 2-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Lipoic acid also plays a critical role in stabilizing and regulating these multienzyme complexes. Many of these dehydrogenases are regulated by reactive oxygen species, mediated through the disulfide bond of the prosthetic lipoyl moiety.Collectively, its functions explain why lipoic acid is required for cell growth, mitochondrial activity and coordination of fuel metabolism.

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MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Cited by 89 publications

References 59 publications

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

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

A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3

Lipoic acid metabolism and mitochondrial redox regulation

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