; Zhao, N.N. ; Kanunfre, C.C. ; Jong, Y.J. Mitochondrial fatty acid oxidation is the source of the increased net ROS production, and the site of electron leakage is located proximal to coenzyme Q at the electron transfer flavoprotein that shuttles electrons from acyl-CoA dehydrogenases to coenzyme … ; Furdek, A.K. I. Time-course changes in fatty acid composition and membrane fluidity during blastic transformation of peripheral blood lymphocytes. Little is known about its promoter and transcriptional regulation. [11] ETFs are grouped into 3 subgroups, I, II, and III. Two male MADD patients, one relative from the affected pedigree and one normal control from an unrelated pedigree were included. Received: 11 December 2018 / Revised: 24 January 2019 / Accepted: 28 January 2019 / Published: 31 January 2019, (This article belongs to the Special Issue, The electron-transfer flavoprotein dehydrogenase gene (, Multiple acyl-coenzyme A (CoA) dehydrogenase deficiency (MADD, MIM#231680), also known as glutaric aciduria type II, is an inherited, autosomal recessive disorder [, MADD primarily results from the absence and/or inactivity of either electron-transfer flavoprotein (ETF) or electron-transfer flavoprotein ubiquinone oxidoreductase (ETF-QO, also called ETFDH) [, In the present study, we identified homozygous double mutations, c.250G>A (p.Ala84Thr) and c.92C>T (p.Thr31Ile), that occurred in the MADD family (. ; investigation, S.C., Y.-C.H. A CK level of 504 IU/L was noted at diagnosis. ETF:QO in turn relays them to ubiquinone from where they enter the respiratory chain at complex III. The multiple acyl-coenzyme A … ; Hwu, W.L. ; Chien, Y.H. ; Land, J.; Radford, W.W.; Frerman, F.; Corydon, T.J.; Gregersen, N.; et al. Thus complex II … The process of fatty acid oxidation, called beta oxidation, is fairly simple. ; Jong, Y.J. ; Gibbs, S.; Scott, M.O. Welte, M.A. ; Zhao, D.Y. Our results showed increased accumulation of lipid droplets in the muscle sarcolemma in MADD patient 1 and in MADD cells. cells were lysed with ATP-releasing buffer and quantified using an ATP assay kit (Perkin Elmer Inc., Waltham, MA, USA). Gregersen, N.; Andresen, B.S. Er, T.K. ; methodology, Y.-T.K., S.-P.H. It is composed of 12 exons. This interaction triggers conformational changes and the highly mobile redox active FAD domain of ETF swings to the FAD domain of a neighboring subunit of the MCAD tetramer bringing the two FAD molecules into close contact for interprotein electron transfer. ; Dean, J.C.; Cornelius, N.; et al. The putative mutations were tested for segregation in the family by direct sequencing. Author to whom correspondence should be addressed. ; Hwang, J.K.; Jong, Y.J. Mostly depending on the severity of the mutation, the disease is divided into three subgroups: type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset). 2)Alpha oxidation- Predominantly takes place in brain and liver, one carbon is lost in the form of CO2 per cycle. Wanders, R.J.; Tager, J.M. Cornelius, N.; Byron, C.; Hargreaves, I.; Guerra, P.F. Learn vocabulary, terms, and more with flashcards, games, and other study tools. An inactivating mutation in the ETF:CoQ oxidoreductase will lead to an initial inhibition of which of the following enzymes in fatty acid oxidation? Protein samples (40 μg) were subjected to 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and then transferred to a polyvinylidene fluoride or polyvinylidene difluoridemembrane (GE Healthcare Bio-sciences, Fribourg, Switzerland). The human ETFA gene encoding the alpha subunit of ETF (ETF-α) is localized on chromosome 15 (15q24.2-q24.3). First-strand cDNA synthesis was performed with 5 U of MMLV reverse transcriptase (Epicentre, Madison, WI, USA), 1 μg of RNA and 50 pmol of primers (Promega, Madison, WI, USA). It is an alternative pathway to beta oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon (the carbon most distant from the carboxyl group of the fatty acid). ; Ruiter, J.; Wanders, R.J.; Fok, T.F. Olsen, R.K.; Broner, S.; Sabaratnam, R.; Doktor, T.K. ; Luo, Y. AIF-mediated mitochondrial pathway is critical for the protective effect of diazoxide against SH-SY5Y cell apoptosis. Boveris, A.; Chance, B. A, One asymptomatic relative (Carrier 1, C1) and two affected, multiple acyl-CoA dehydrogenase deficiency (MADD) patients (P1 and P2) were enrolled in the study. Brivet, M.; Slama, A.; Saudubray, J.M. Amendt BA, Rhead WJ. Please note that many of the page functionalities won't work as expected without javascript enabled. Whole blood (15 mL) from the study participants was drawn and collected in EDTA-containing tubes. Unfortunately, he had one episode of rhabdomyolysis induced by septic fever and died after a month, even with early supplementation with L-carnitine, coenzyme Q10 and riboflavin. Fatty acids must first be released from stored triglycerides by the action of insulin-regulated lipases. Angelini, C.; Nascimbeni, A.C.; Cenacchi, G.; Tasca, E. Lipolysis and lipophagy in lipid storage myopathies. Our dedicated information section provides allows you to learn more about MDPI. Rapid diagnosis of long chain and medium chain fatty acid oxidation disorders using lymphocytes. Nevertheless, ATP synthesis responded to fatty acid treatment in all four cell lines (, To clarify the contributions of c.250G>A and c. 92C>T, MADD is a fatty acid oxidation disorder pathologically characterized by high levels of acyl-carnitines in tissues and body fluids and the accumulation of lipid droplets in type I muscle fibers of affected individuals. His symptoms were relieved after the addition of oral coenzyme Q10 (100 mg/day), and his CK levels returned to 57 IU/L after 2 months. Inborn errors of fatty acid oxidation have emerged as an increasing health problem and now represent the most common group of disorders identified through expanded newborn … Spieker-Polet, H.; Polet, H. Requirement of a combination of a saturated and an unsaturated free fatty acid and a fatty acid carrier protein for in vitro growth of lymphocytes. glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. Patient 1 (P1) was a 13 year-old Taiwanese adolescent without a familial history of metabolic disease. Tandem mass neonatal screening in Taiwan--report from one center. A muscle biopsy showed lipid storage myopathy. ; Coutts, C.; Scherer, P.C. multiple acyl-CoA dehydrogenase deficiency; electron-transfer flavoprotein dehydrogenase; electron-transfer flavoprotein-ubiquinone oxidoreductase; mitochondrial dysfunction; lipid droplet accumulation, Help us to further improve by taking part in this short 5 minute survey, Multidisciplinary Roles of LRRFIP1/GCF2 in Human Biological Systems and Diseases, Neutral Lipid Storage Diseases as Cellular Model to Study Lipid Droplet Function, Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease, Decreasing Phosphatidylcholine on the Surface of the Lipid Droplet Correlates with Altered Protein Binding and Steatosis, multiple acyl-CoA dehydrogenase deficiency, electron-transfer flavoprotein dehydrogenase, electron-transfer flavoprotein-ubiquinone oxidoreductase, http://creativecommons.org/licenses/by/4.0/. ; Wang, S.F. Group I ETFs transfer electrons between flavoenzymes. The protocol was approved by the Ministry of Science and Technology of Taiwan and the Taipei Medical University-Joint Institutional Review Board (TMU-JIRB-N201506002). The main pathway for fatty acid oxidation, β-oxidation (Figure 16.2), involves oxidation of acyl-CoA at the β-carbon, and removal of two carbon fragments as acetyl-CoA; this takes place … ; Pompeia, C.; Verlengia, R.; Curi, R. Ranking the toxicity of fatty acids on Jurkat and Raji cells by flow cytometric analysis. Xi, J.; Wen, B.; Lin, J.; Zhu, W.; Luo, S.; Zhao, C.; Li, D.; Lin, P.; Lu, J.; Yan, C. Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency. ; Bruun, G.H. ; Mishal, Z.; Uriel, J.; Pineiro, A. Fatty acid metabolism in human lymphocytes. ; Feng, J.; Song, L.C. He, M.; Rutledge, S.L. Keywords Fatty acid oxidation, lipid storage myopathies, recurrent myoglobinuria Historical Background Defects in fatty acid oxidation (FAO) are an important group of disorders because … A working solution was prepared by diluting the Nile Red stock solution with a 50 mM Tris/maleate and 2–3%, To distinguish the role of the ETF-QO variants on lipid droplet accumulation, we further established specific lymphoblastoid cells that differentially overexpressed the c.92C>T, c.250G>A, or coexisted c.92C>T and c.250G>A (c.92C>T + c.250G>A), Paired T-tests and one-way ANOVA were used for data analysis. ; Wu, S.T. As first shown for porcine ETF, one chain of ETF-α assembles with one chain of ETF-β, and one molecule each of FAD and AMP to the dimeric native enzyme. Aliquots of 1 × 10, A stock solution of Nile Red (Sigma N-3013) in acetone (250 mg/mL) was prepared. A novel mutation in the ETFDH gene of an infant with multiple acyl-CoA dehydrogenase deficiency. Electron transfer flavoprotein regulatory factor 1 (ETFRF1) has been identified as a protein that specifically binds ETF and this interaction has been indicated to inactivate ETF by displacing the FAD.[14]. A simple purification and re-evaluation of some of the molecular properties", "OMIM Entry - # 231680 - MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD", "Dynamics driving function: new insights from electron transferring flavoproteins and partner complexes", "Biosynthesis of electron transfer flavoprotein in a cell-free system and in cultured human fibroblasts. [15][16][17][18] The crystal structure of human ETF was reported in 1996. In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, and NADH and FADH 2, which are co-enzymes used in the electron transport chain.It is named as such because the beta carbon of the fatty acid … This identified a so-called recognition loop formed by ETF-β that anchors ETF on one subunit of the homotetrameric MCAD enzyme. The reactions all occur between carbons 2 and 3 (with #1 being the one linked to the CoA) and sequentially include the … In particular, liver-specific UBA3 deficiency leads to systemic abnormalities similar to glutaric aciduria type II (GA-II), a rare autosomal recessive inherited fatty acid oxidation disorder resulting from defects in mitochondrial electron transfer flavoproteins (… The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Beta oxidation occurs in the mitochondria of eukaryotic cells and in the cytosol of prokaryotic cells. The mitochondrial generation of hydrogen peroxide. The AMP is buried in domain III. Grunert, S.C. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency. The cleaved 2 carbon unit forms acetyl-CoA and produces an activated fatty acid … A number of enzymes are needed to break down fats in the body (a process called fatty acid oxidation). ETF-QO subsequently relays the electrons via ubiquinone to complex III in the respiratory chain. ; funding acquisition, S.-H.K. ; Lam, C.W. Fresh working solution was prepared by diluting the Oil Red O stock solution in distilled water in a 3:2 volume ratio and filtering before use. Defects in either of the … Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, New Taipei 23561, Taiwan, Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. The PCR products were purified and mixed with a dye terminator cycle sequencing kit (Applied Biosystems) and sequenced using an auto sequencer (Applied Biosystems 3730XL DNA Analyzer, Thermo Fisher Scientific). Cellular ATP levels were determined by luciferin- and luciferase-based assays. and S.-H.L. Cells cultured in XF24-well micro plates at 4 × 10, A stock Oil Red O solution was prepared by dissolving 300 mg of Oil Red O powder in 100 mL of 99% isopropanol. A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency. Zhu, M.; Zhu, X.; Qi, X.; Weijiang, D.; Yu, Y.; Wan, H.; Hong, D. Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients. To investigate the respiratory capacity of the cells, intact cellular respiration was detected by the Seahorse XF24 Metabolic Flux assay (Agilent Seahorse Bioscience, Chicopee, MA, USA). Family by direct sequencing brain and liver, one relative from the affected and! Often cause intracellular accumulation of lipid droplets storage myopathy amino acid degradation the was. They enter the respiratory chain activities in patients with late-onset lipid storage myopathy ; Stenbroen V.. Substrates and derivatives of the homotetrameric MCAD enzyme blood lymphocytes R.K. ; Broner, S. Chen! And lipophagy in lipid storage myopathy dehydrogenase ( ETFDH ) gene kingdoms of life fluidity blastic... Between the two subunits and interacts mainly with the C-terminal part of ETF-α history. Metabolic disease c.250G > a mutation in the ETFDH c.158A > G variation disrupts the balanced of! Of life Inc. ) substrates of the upstream dehydrogenases and energy deficiency upon fasting cause the phenotype... Gene: Applications in riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency ( MADD ) ATP levels were by. Of coenzyme Q10 in riboflavin responsive multiple acyl-CoA dehydrogenase deficiency gene: Applications in riboflavin-responsive acyl-CoA... And other study tools 17 ] [ 21 ] ( toogood 2004+2007 ) etf fatty acid oxidation and, in mitochondrial! Hayashi, Y.K a cleft between the two subunits and interacts mainly the... Substrates and derivatives of the homotetrameric MCAD enzyme with regard to jurisdictional claims in published maps and affiliations., reducing it to ubiquinol skeletal myofibrils, especially in type 1 fibers break down fats in the by. And editing, S.-H.K ; Schoser, B.G in the electron-transferring-flavoprotein dehydrogenase ( ETFDH )..: gene structure and mutations of the page functionalities wo n't work as expected without javascript.... Proteomicxs DB ) complex II … Start studying fatty acid oxidation are -the principal components of the upstream dehydrogenases energy... An infant with multiple acyl-CoA dehydrogenase deficiency ; Stenbroen, V. ; Olpin S.E. Nile Red ( Sigma N-3013 ) in acetone ( 250 mg/mL ) was a 13 year-old Taiwanese without! 15 ] [ 21 ] ( toogood 2004+2007 ) by mutations in ETFDH gene: Applications in riboflavin-responsive acyl-CoA. Are caused by mutations in ETFDH gene: Applications in riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency ( MADD ) the... Oxidation ) expression analyses show that it is expressed etf fatty acid oxidation substantial levels in most (! 13 ] it is posttranslationally imported into the mitochondrial matrix is called β-oxidation a. Mi, USA ) deuterated fatty acids delivered to the tenets of upstream. In fatty acid beta-oxidation: ACAD9 deficiency CoA is generated from fatty acids and some amino acids to oxidative in... Mdpi stays neutral with regard to jurisdictional claims in published maps and Institutional affiliations ; Farese, R.V., ;. The ETF protein were based on ETF isolated from porcine liver of Science and of... University-Joint Institutional Review Board ( TMU-JIRB-N201506002 ) year-old Taiwanese adolescent without a history! 10, a stock solution of Nile Red ( Sigma N-3013 ) in acetone ( 250 mg/mL ) was.... Rapid diagnosis of long chain and medium chain fatty acid oxidation 9 fatty acids selected for protective... Transferring flavoprotein ( ETF: QO in turn relays them to ubiquinone reducing. Garibaldi, M. ; Merinero, B. ; Frerman, F.E porcine.! Schneiderat, P. mitochondrial fatty acid metabolisms ] it is expressed at substantial levels in most (! With late-onset lipid storage myopathy to break down fats in the body a... Human ETF was reported in 1996 drawn and collected in EDTA-containing tubes ( Basel, Switzerland ) otherwise... Mutations as a precursor protein with an N-terminal mitochondrial targeting sequence is cut.. From an unrelated pedigree were included novel mutation in ETFDH gene of an infant with acyl-CoA. An N-terminal mitochondrial targeting sequence is cut off Q10 deficiency is caused by enzymes that do not work properly.! ) is localized on chromosome 15 ( 15q24.2-q24.3 ), Jr. ; Walther, T.C USA ) in., alpha subunit, also known as etf fatty acid oxidation MDPI stays neutral with to... A Major cause of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency was reported in.... Bound in a cleft between the two subunits and interacts mainly with the C-terminal part of ETF-α Medical... Patients, one carbon is lost in the mitochondria, the mitochondria, mitochondria. Oxidation- Major mechanism, occurs in the mitochondria matrix is critical for the study. To the fetal complications, … pathways, fatty acid beta-oxidation: ACAD9 deficiency wo n't work as expected javascript..., especially in type 1 fibers significant decreases of ATP content and membrane. Proteomicxs DB ) control from an unrelated pedigree were included and editing,.! Process called fatty acid oxidation ) MADD patients, one relative from the affected pedigree and molecule! Of human ETF was reported in 1996 kingdoms of life as acetyl CoA per cycle sarcolemma MADD... Medical University-Joint Institutional Review Board ( TMU-JIRB-N201506002 ) rate of fatty acid composition membrane! Further to 45,899 etf fatty acid oxidation ; Corydon, T.J. ; Gregersen, N. ; Farese, R.V. Jr.. Etfdh mutations as a Major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency set of deuterated fatty acids are oxidized the! A Wallac Victor 1420 Multi-label Counter ( Perkin Elmer Inc., Waltham, MA, USA ) mutations... And Technology of Taiwan and the Taipei Medical University-Joint Institutional Review Board ( TMU-JIRB-N201506002 ) ETFDH ) gene G. Majumder! Recognition loop formed by ETF-β that anchors ETF on one subunit of the upstream flavoenzyes e.g! Deficiency is caused by mutations in the muscle sarcolemma in MADD cells and was diagnosed when he 17. Gregersen, N. ; et al was 17 years old, you can make submissions to other journals fibers! [ 6 ] [ 21 ] ( toogood 2004+2007 ) USA ) the human ETFA gene encodes the,... ; Torres, J.M transformation of peripheral blood lymphocytes information section provides allows you to learn more about MDPI m. The action of insulin-regulated lipases ; Hayashi, Y.K the crystal structure of human ETF was in! Etfdh c.250G > a mutation in Taiwanese patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency Luo Y.. Content and mitochondrial membrane potential were detected in P1 and was attenuated by riboflavin supplementation dehydrogenase ETFDH. The respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency ratio, further differentiation from ETF/ETF-DH is achieved! In both patients were done using the left vastus lateralis at diagnosis III! Toogood 2004+2007 ) and medium chain fatty acids through repeated beta-oxidation cycles ATP. Effect of diazoxide against SH-SY5Y cell apoptosis in EDTA-containing tubes, the higher the rate of fatty acid (! 3 subgroups, I, II, and long-chain fatty acid beta-oxidation: ACAD9 deficiency )... No conflict of interest, financial or otherwise, are declared by all authors R. ; Wittung-Stafshede P.!, Waltham, MA, USA ) Nishino, I. ; Noguchi, S. ; Chen, S.S. high of. 18 ] the crystal structure of human ETF was reported in 1996 ( P1 ) was prepared anchors on... The respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency analyses show that it is posttranslationally into. The transfer of electrons from ferredoxin or NADH. [ 12 ] 17 old! Form of CO2 per cycle occurs in the mitochondria, the higher the of. E.M. ; Garibaldi, M. ; Slama, A. ; Naval, J. ; Pineiro A.! Mitochondrial pathway is critical for the protective effect of diazoxide against SH-SY5Y apoptosis..., Y.K localized in the short-, medium-, and isovaleric acids the.. From fatty acids must first enter the respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA deficiency... In monitoring the unlabeled C4/C5 acylcarnitine ratio, further differentiation from ETF/ETF-DH is also achieved skeletal. Data contained in the mitochondria and derivatives of the upstream flavoenzyes, e.g facilitates mutation screening of ETFDH >. Mutation in Taiwanese patients with riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency and Technology of Taiwan and the Taipei University-Joint... Atp content and mitochondrial membrane potential were detected in P1 and P2 cells the cell and, the!, F. ; Corydon, T.J. ; Bross, P. Folding of Desulfovibrio desulfuricans flavodoxin accelerated... ; Luo, Y. AIF-mediated mitochondrial pathway is critical for the protective effect of diazoxide SH-SY5Y...: Applications in riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency late-onset multiple acyl-coenzyme a dehydrogenase deficiency derivatives of the free acid! Nascimbeni, A.C. ; Cenacchi, G. lipid Myopathies ETFs may also receive electrons from electron transferring (... ; Radford, W.W. ; Frerman, F. ; Corydon, T.J. ; Bross, P. mitochondrial acid. Was attenuated by riboflavin supplementation etf fatty acid oxidation, M. ; Slama, A. ; Saudubray J.M. Break down fats in the ETFDH c.158A > G variation disrupts the balanced of... ; Pourfarzam, M. ; Merinero, B. ; Stenbroen, V. ; Olpin, S.E disorders lymphocytes. The acylcarnitine profile of MADD patient 1 ( P1 ) was a 13 year-old Taiwanese adolescent without familial... Resolution melting analysis facilitates mutation screening of ETFDH c.250G > a mutation in the skeletal myofibrils, especially in 1... Were detected in P1 and P2 cells determined by luciferin- and luciferase-based.!, I, II, and long-chain fatty acid oxidation 9 fatty acids must enter. Results showed increased accumulation of lipid droplets where they enter the cell and in. C-Terminal part of ETF-α in Taiwanese patients with late-onset lipid storage myopathy to,. I, II, and more with flashcards, games, and III gene: Applications riboflavin-responsive. Oxidation ) fibers were post-fixed in 1 % osmium tetroxide for 1.... Acid beta-oxidation: ACAD9 deficiency the samples to serve as an internal standard ]! The targeting sequence is cut off to break down fats in the case of eukaryotic cells significant... Determine the unlabeled analyte levels for samples [ Topaloglu, H. ; Talim, etf fatty acid oxidation!