Novel MECR Mutation in Childhood-Onset Dystonia, Optic Atrophy, and Basal Ganglia Signal Abnormalities

Görükmez, Orhan; Görükmez, Özlem; Havalı, Cengiz

doi:10.1055/s-0039-1688767

Cited by 14 publications

(9 citation statements)

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“…Human mutations in genes encoding enzymes of the mtFAS pathway are rare, but continue to be discovered ( Gorukmez et al, 2019 ; Heimer et al, 2016 ; Li et al, 2020 ). Intriguingly, patients with Mecr mutations exhibit muscle weakness and we show herein that mtFAS mutation interferes with the normal differentiation of cultured myoblasts ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

“…Inducible knockout of the mitochondrial malonyl CoA-acyl carrier protein transacylase ( Mcat ) using a Cre driver that expresses in most tissues in mice results in a severe phenotype characterized by weight loss, reduced muscle strength, and shortened lifespan despite the persistence of residual MCAT protein ( Smith et al, 2012 ). Knockout of the mitochondrial 2-enoyl thioester reductase, Mecr , is lethal in mice due to a placental defect ( Nair et al, 2017 ), while the inducible knockout of Mecr specifically in Purkinje cells leads to loss of this cell population and recapitulates many phenotypes of MePaN syndrome, the human disease caused by Mecr mutation ( Gorukmez et al, 2019 ; Heimer et al, 2016 ; Nair et al, 2018 ). Similarly, Mecr knockdown has been shown to inhibit the growth of hepatocellular carcinoma cells ( Cai et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

Nowinski¹,

Solmonson

Rusin

et al. 2020

eLife

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Cells harbor two systems for fatty acid synthesis, one in the cytoplasm (catalyzed by fatty acid synthase, FASN) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, especially in higher eukaryotes, with the major product(s), metabolic roles, and cellular function(s) being essentially unknown. Here we show that hypomorphic mtFAS mutant mouse skeletal myoblast cell lines display a severe loss of electron transport chain (ETC) complexes and exhibit compensatory metabolic activities including reductive carboxylation. This effect on ETC complexes appears to be independent of protein lipoylation, the best characterized function of mtFAS, as mutants lacking lipoylation have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. Together, these data suggest that ETC activity in mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid synthesis with the oxidation of carbon fuels.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

Nowinski¹,

Solmonson

Rusin

et al. 2020

eLife

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“…MRI analyses revealed basal ganglia signal abnormalities, cerebral and cerebellar atrophy. The patient was found to carry compound heterozygous mutation in MECR (Gorukmez and others 2019). The cerebellar atrophy and epilepsy features were not previously reported in MECR defect patients but are common in disorders caused by defects in LA synthesis or attachment (Mayr and others 2014).…”

Section: Human Patients With Defects In Mtfas and Related Pathwaysmentioning

confidence: 99%

Mitochondrial Fatty Acids and Neurodegenerative Disorders

2020

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Fatty acids in mitochondria, in sensu stricto, arise either as β-oxidation substrates imported via the carnitine shuttle or through de novo synthesis by the mitochondrial fatty acid synthesis (mtFAS) pathway. Defects in mtFAS or processes involved in the generation of the mtFAS product derivative lipoic acid (LA), including iron-sulfur cluster synthesis required for functional LA synthase, have emerged only recently as etiology for neurodegenerative disease. Intriguingly, mtFAS deficiencies very specifically affect CNS function, while LA synthesis and attachment defects have a pleiotropic presentation beyond neurodegeneration. Typical mtFAS defect presentations include optical atrophy, as well as basal ganglia defects associated with dystonia. The phenotype display of patients with mtFAS defects can resemble the presentation of disorders associated with coenzyme A (CoA) synthesis. A recent publication links these processes together based on the requirement of CoA for acyl carrier protein maturation. MtFAS defects, CoA synthesis- as well as Fe-S cluster-deficiencies share lack of LA as a common symptom.

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“…Inducible knockout of the mitochondrial malonyl CoA-acyl carrier protein transacylase (Mcat) using a Cre driver that expresses in most tissues in mice results in a severe phenotype characterized by weight loss, reduced muscle strength, and shortened lifespan despite the persistence of residual MCAT protein (Smith et al, 2012). Knockout of the mitochondrial 2-enoyl thioester reductase, Mecr, is lethal in mice due to a placental defect (Nair et al, 2017), while the inducible knockout of Mecr specifically in Purkinje cells leads to loss of this cell population and recapitulates many phenotypes of MePaN syndrome, the human disease caused by Mecr mutation (Gorukmez et al, 2019;Heimer et al, 2016;Nair et al, 2018). Similarly, Mecr knockdown has been shown to inhibit the growth of hepatocellular carcinoma cells (Cai et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolism

Nowinski

Solmonson²,

Rusin

et al. 2020

Preprint

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19Cells harbor two systems for fatty acid synthesis, one in the cytoplasm (catalyzed by fatty 20 acid synthase, FASN) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is 21 poorly characterized, especially in higher eukaryotes, with the major product(s), metabolic roles, 22 and cellular function(s) being essentially unknown. Here we show that hypomorphic mtFAS 23 mutants display a severe loss of electron transport chain (ETC) complexes and exhibit 24 compensatory metabolic activities including reductive carboxylation. This effect on ETC 25 complexes appears to be independent of protein lipoylation, the best characterized function of 26 2 mtFAS, as mutants lacking lipoylation have an intact ETC. Finally, mtFAS impairment blocks the 27 differentiation of skeletal myoblasts in vitro. Together, these data suggest that ETC activity in 28 mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid 29 synthesis with the oxidation of carbon fuels. 30 31 Keywords: 32 Mitochondria, fatty acid synthesis, electron transport chain, reductive carboxylation, lipoylation, 33 TCA cycle, metabolism, respiration, OXPHOS, muscle 34 35 Abbreviations: 36 ACP -acyl carrier protein, ETC -electron transport chain, FAS -fatty acid synthesis, FASN -37 fatty acid synthase, LYRM -leucine tyrosine arginine motif, mtFAS -mitochondrial fatty acid 38 synthesis, OGDH -oxoglutarate dehydrogenase, OXPHOS -oxidative phosphorylation, PAGE 39 -polyacrylamide gel electrophoresis, PDH -pyruvate dehydrogenase, TCA -tricarboxylic acid 40 41 Introduction 42 43Fatty acids play diverse cellular roles, including providing the hydrophobic tails of membrane 44 phospholipids, energy storage in the form of triglycerides, and as cell signaling molecules. Aside 45 from the import of exogenous fatty acids, mammalian cells use the well-known and well-studied 46 cytoplasmic enzyme fatty acid synthase (FASN) to make palmitate, which is further modified to 47 form the diverse array of cellular fatty acids (Smith, 1994). However, it is much less appreciated 48 that mitochondria also harbor a spatially and genetically distinct fatty acid synthesis pathway 49 (mtFAS) (reviewed in (Nowinski et al., 2018)). In contrast to FASN, which is a very large protein 50 that contains several domains and encompasses all of the enzymatic activities necessary for 51 FAS condensed in a single polypeptide chain, the mtFAS pathway is comprised of at least six 52 enzymes all encoded by separate genes. These enzymes catalyze sequential steps to achieve 53 one cycle of two-carbon addition to a growing acyl chain ( Figure 1A). The nascent fatty acids 54 are covalently attached to the mitochondrial acyl carrier protein (ACP), which acts as a soluble 55 scaffold upon which the acyl chains are built. In each cycle of the pathway, malonyl-CoA is 56 converted to malonyl-ACP, which then undergoes a condensation reaction with the growing fatty 57 acyl chain on ACP, extending the chain by two carbons and releasing a CO2 molecule. 58Thereafter, the remaining...

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Novel MECR Mutation in Childhood-Onset Dystonia, Optic Atrophy, and Basal Ganglia Signal Abnormalities

Cited by 14 publications

References 1 publication

Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

Mitochondrial Fatty Acids and Neurodegenerative Disorders

Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolism

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