Riboflavin metabolism: role in mitochondrial function

Abstract

Riboflavin, known as vitamin B2, a water-soluble vitamin, is an essential nutrient in vertebrates, hence adequate dietary intake is imperative. Riboflavin plays a role in a variety of metabolic pathways, serving primarily as an integral component of its crucial biologically active forms, the flavocoenzymes flavin adenine dinucleotide and flavin mononucleotide. These flavocoenzymes ensure the functionality of numerous flavoproteins including dehydrogenases, oxidases, monooxygenases, and reductases, which play pivotal roles in mitochondrial electron transport chain, β-oxidation of fatty acids, redox homeostasis, citric acid cycle, branched-chain amino acid catabolism, chromatin remodeling, DNA repair, protein folding, and apoptosis. Unsurprisingly, impairment of flavin homeostasis in humans has been linked to various diseases including neuromuscular and neurological disorders, abnormal fetal development, and cardiovascular diseases. This review presents an overview of riboflavin metabolism, its role in mitochondrial function, primary and secondary flavocoenzyme defects associated with mitochondrial dysfunction, and the role of riboflavin supplementation in these conditions.

Keywords

Mitochondria / riboflavin / flavocoenzymes / primary flavocoenzyme defects / secondary flavoproteome defects / riboflavin responsive disorders

References

[1] Lienhart WD,Macheroux P.The human flavoproteome..Arch Biochem Biophys2013;535:150-62 PMCID:PMC3684772

[2] Joosten V.Flavoenzymes..Curr Opin Chem Biol2007;11:195-202

[3] Balasubramaniam S,Rahman S.Disorders of riboflavin metabolism..J Inherit Metab Dis2019;42:608-19

[4] Kennedy DO.B Vitamins and the brain: mechanisms, dose and efficacy-a review..Nutrients2016;8:68 PMCID:PMC4772032

[5] Barile M,Leone P,Indiveri C.Riboflavin transport and metabolism in humans..J Inherit Metab Dis2016;39:545-57

[6] Henriques BJ,Gomes CM.Preedy VR.Riboflavin and b-oxidation flavoenzymes..B vitamins and folate: chemistry, analysis, function and effects (Food and nutritional components in focus series No. 4).2013;CambridgeThe Royal Society of Chemistry Publishing611-30

[7] Mosegaard S,Bross P,Gregersen N.Riboflavin Deficiency-Implications for general human health and inborn errors of metabolism..Int J Mol Sci2020;21:E3847 PMCID:PMC7312377

[8] McCormick DB.Two interconnected B vitamins: riboflavin and pyridoxine..Physiol Rev1989;69:1170-98

[9] Zempleni J,McCormick DB.Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans..Am J Clin Nutr1996;63:54-66

[10] Powers HJ.Riboflavin (vitamin B-2) and health..Am J Clin Nutr2003;77:1352-6130

[11] Chastain JL.Flavin catabolites: identification and quantitation in human urine..Am J Clin Nutr1987;46:830-4

[12] Suomalainen A.Mitochondrial diseases: the contribution of organelle stress responses to pathology..Nat Rev Mol Cell Biol2017;19:77-92

[13] Gorman GS,DiMauro S,Kogaet Y.Mitochondrial diseases..Nat Rev Dis Primers2016;2:16080

[14] Hatefi Y.The mitochondrial electron transport and oxidative phosphorylation system..Annu Rev Biochem1985;54:1015-69

[15] Van Houten B,Santos JH.Role of mitochondrial DNA in toxic responses to oxidative stress..DNA Repair (Amst)2006;5:145-52

[16] Ross WN.Understanding calcium waves and sparks in central neurons..Nat Rev Neurosci2012;13:157-68 PMCID:PMC4501263

[17] Niyazov DM,Frye R.Primary mitochondrial disease and secondary mitochondrial dysfunction: importance of distinction for diagnosis and treatment..Mol Syndromol2016;7:122-37 PMCID:PMC4988248

[18] Yonezawa A,Katsura T.Identification and functional characterization of a novel human and rat riboflavin transporter, RFT1..Am J Physiol Cell Physiol2008;295:C632-41

[19] Yonezawa A.Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52..Mol Aspects Med2013;34:693-701

[20] Yamamoto S,Ohta KY,Maeda J.Identification and functional characterization of rat riboflavin transporter 2..J Biochem2009;145:437-43

[21] Yao Y,Yoshimatsu H,Katsura T.Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain..J Nutr2010;140:1220-6

[22] Bosch AM,Ijlst L,van der Pol WL.Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment..J Inherit Metab Dis2011;34:159-64 PMCID:PMC3026695

[23] Green P,Crow YJ,Riphagenet S.Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54..Am J Hum Genet2010;86:485-9 PMCID:PMC2833371

[24] Dipti S,Livingston JH,Miller M.Brown-Vialetto-Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease..Brain Dev2005;27:443-6

[25] Manole A.Riboflavin transporter deficiency neuronopathy. In: GeneReviews® [Internet].1993-2020;Seattle (WA)University of Washington

[26] O’Callaghan B,Houlden H.An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency..J Inherit Metab Dis2019;42:598-607

[27] Chiong MS,Carpenter K,Ho G.Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency..Mol Genet Metab2007;92:109-14

[28] Ho G,Masuda S,Sim KG.Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B..Hum Mutat2011;32:E1976-84

[29] Mosegaard S,Flybjerg KF,Gregersen N.An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency..Mol Genet Metab2017;122:182-8

[30] Schiff M,Acquaviva-Bourdain C.SLC25A32 mutations and riboflavin-responsive exercise intolerance..N Engl J Med2016;374:795-7 PMCID:PMC4867164

[31] Hellebrekers DMEI,Theunissen TEJ,Gottschalk RW.Novel SLC25A32 mutation in a patient with a severe neuromuscular phenotype..Eur J Hum Genet2017;25:886-8 PMCID:PMC5520074

[32] Santoro V,Vriens K,Bernthaler A.SLC25A32 sustains cancer cell proliferation by regulating flavin adenine nucleotide (FAD) metabolism..Oncotarget2020;11:801-12 PMCID:PMC7055544

[33] Giancaspero TA,Brizio C,Fiorino GM.Remaining challenges in cellular flavin cofactor homeostasis and flavoprotein biogenesis..Front Chem2015;22:30 PMCID:PMC4406087

[34] Olsen RKJ,Giancaspero TA,Boczonadi V.Riboflavin responsive and-non-responsive mutations in FAD synthase cause multiple acyl-CoA dehydrogenase and combined respiratory-chain deficiency..Am J Hum Genet2016;98:1130-45 PMCID:PMC4908180

[35] Torchetti EM,Colella M,Giancaspero TA.Mitochondrial localization of human FAD synthetase isoform 1..Mitochondrion2010;10:263-73

[36] Giancaspero TA,Panebianco C,Miccolis A.FAD synthesis and degradation in the nucleus create a local flavin cofactor pool..J Biol Chem2013;288:29069-80 PMCID:PMC3790006

[37] Leone P,Barbiroli A,Tolomeo M.Bacterial production, characterization and protein modeling of a novel monofunctional isoform of FAD synthase in humans: an emergency protein?.Molecules2018;23:116-31 PMCID:PMC6017331

[38] Torchetti EM,Galluccio M,Giancaspero TA.Human FAD synthase (isoform 2): a component of the machinery that delivers FAD to apo-flavoproteins..FEBS J2011;278:4434-49

[39] Taylor RW,Griffin H,Duff J.Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies..JAMA2014;312:68-77 PMCID:PMC6558267

[40] Auranen MA,Piirilä P,Salmi T.Patient with multiple acyl-CoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy..Neuromuscul Disord2017;27:581-4

[41] Yildiz Y,Sivri HS,Nygaard HH.Post-mortem detection of FLAD1 mutations in 2 Turkish siblings with hypotonia in early infancy..Neuromuscul Disord2018;28:787-90

[42] Ryder B,Nochi Z,Barile M.A novel truncating FLAD1 variant, causing multiple Acyl-CoA dehydrogenase deficiency (MADD) in an 8-year-old boy..JIMD Rep2019;45:37-44 PMCID:PMC6336555

[43] García-Villoria J,Tort F,Ugarteburu O.FLAD1, encoding FAD synthase, is mutated in a patient with myopathy, scoliosis and cataracts..Clin Genet2018;94:592-3

[44] Muru K,Künnapas K,Nochi Z.FLAD1-associated multiple acyl-CoA dehydrogenase deficiency identified by newborn screening..Mol Genet Genomic Med2019;7:e915 PMCID:PMC6732309

[45] Yamada K,Kobayashi H,Fukuda S.Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: a case report..Brain Dev2019;41:638-42

[46] Karthikeyan S,Mseeh F,Osterman AL.Crystal structure of human riboflavin kinase reveals a beta barrel fold and a novel active site arch..Structure2003;11:265-73

[47] Yazdanpanah B,Tchikov V,Pongratz C.Riboflavin kinase couples TNF receptor 1 to NADPH oxidase..Nature2009;460:1159-63

[48] Zhang J,Zou D,Wan T.Cloning and functional characterization of ACAD-9, a novel member of human acyl-CoA dehydrogenase family..Biochem. Biophys Res Commun2002;297:1033-42

[49] Schiff M,Xia CW,Goetzman ES.Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency..Hum Mol Genet2015;24:3238-47 PMCID:PMC4424958

[50] Nouws J,Nijtmans LG.ACAD9, a complex I assembly factor with a moonlighting function in fatty acid oxidation deficiencies..Hum Mol Genet2014;23:1311-9

[51] Repp BM,Alston CL,Haack TB.Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?.Orphanet J Rare Dis2018;13:120 PMCID:PMC6053715

[52] Oey NA,Ijlst L,Vekemans M.Acyl-CoA dehydrogenase 9 (ACAD 9) is the long-chain acyl-CoA dehydrogenase in human embryonic and fetal brain..Biochem Biophys Res Commun2006;21;346:33-7

[53] Lemire BD.Evolution of FOXRED1, an FAD-dependent oxidoreductase necessary for NADH: Ubiquinone oxidoreductase (Complex I) assembly..Biochim. Biophys Acta2015a;1847:451-7

[54] Lemire BD.Glutathione metabolism links FOXRED1 to NADH: ubiquinone oxidoreductase (complex I) deficiency: a hypothesis..Mitochondrion2015b;24:105-12

[55] Barbosa-Gouveia S,Borges F,Wintjes L.Identification and characterization of new variants in FOXRED1 gene expands the clinical spectrum associated with mitochondrial complex I deficiency..J Clin Med2019;8:1262 PMCID:PMC6723710

[56] Calvo SE,Compton AG,Crawford G.High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency..Nat Genet2010;42:851-8 PMCID:PMC2977978

[57] Fassone E,Taanman JW,Sadowski MI.FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy..Hum Mol Genet2010;19:4837-47 PMCID:PMC4560042

[58] Haack TB,Herzer M,Danhauser K.Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9..J Med Genet2012;49:83-9

[59] Zurita Rendón O,Horvath R.A mutation in the flavin adenine dinucleotide-dependent oxidoreductase FOXRED1 results in cell-type-specific assembly defects in oxidative phosphorylation complexes I and II..Mol Cell Biol2016;36:2132-40 PMCID:PMC4968213

[60] Apatean D,Brunel-Guitton C,Bai R.Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency..Mol Genet Metab Rep2019;18:32-8 PMCID:PMC6349952

[61] Formosa LE,Frazier AE,Stait TL.Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I..Hum Mol Genet2015;24:2952-65

[62] Bentinger M,Dallner G.The antioxidant role of coenzyme Q..Mitochondrion.2007;7 Suppl:S41-50

[63] Turunen M,Dallner G.Metabolism and function of coenzyme Q..Biochim Biophys Act.2004;1660:171-99

[64] Acosta Lopez MJ,Canton M,Morbidoniet V.Vanillic acid restores coenzyme q biosynthesis and ATP production in human cells lacking COQ6..Oxid Med Cell Longe2019;2019:3904905 PMCID:PMC6652073

[65] Heeringa SF,Chaki M,Sloan AJ.COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness..J Clin Invest2011;121:2013-24 PMCID:PMC3083770

[66] Cao Q,Xu H,Sun L.Coenzyme Q (10) treatment for one child with COQ6 gene mutation induced nephrotic syndrome and literature review..Zhonghua Er Ke Za Zhi2017;55:135-8(in Chinese)

[67] Gigante M,Santangelo L,Acosta MJ.Further phenotypic heterogeneity of CoQ10 deficiency associated with steroid resistant nephrotic syndrome and novel COQ2 and COQ6 variants..Clin Genet2017;92:224-6

[68] Park E,Kang HG,Won NH.COQ6 mutations in children with steroid-resistant focal segmental glomerulosclerosis and sensorineural hearing loss..Am J Kidney Di2017;70:139-44

[69] Li GM,Shen Q,Zhai YH.Gene mutation analysis in 12 Chinese children with congenital nephrotic syndrome..BMC Nephro2018;19:382 PMCID:PMC6311020

[70] Stanczyk M,Lipska-Zietkiewicz B.CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy-a case report..Pediatr Nephrol2018;33:2383-7 PMCID:PMC6208703

[71] Yuruk Yildirim Z,Uyguner O,Yavuz S.Primary coenzyme Q10 Deficiency-6 (COQ10D6): two siblings with variable expressivity of the renal phenotype..Eur J Med Genet2020;63:103621

[72] Koyun M,Akman S.CoenzymeQ10 therapy in two sisters with CoQ6 mutations with long-term follow-up..Pediatr Nephrol2019;34:737-8

[73] Ozeir M,Webert H,Fontecave M.Coenzyme Q biosynthesis: Coq6 is required for the C5-hydroxylation reaction and substrate analogs rescue Coq6 deficiency..Chem Biol2011;18:1134-42

[74] Ozaltin F.Primary coenzyme Q10 (CoQ 10) deficiencies and related nephropathies..Pediatr Nephrol2014;29:961-9

[75] Herrmann JM.Mitochondrial disulfide relay: redox-regulated protein import into the intermembrane space..J Biol Chem2012;10;287:4426-33 PMCID:PMC3281597

[76] Bihlmaier K,Terziyska N,Hell K.The disulfide relay system of mitochondria is connected to the respiratory chain..J Cell Biol2007;179:389-95 PMCID:PMC2064786

[77] Di Fonzo A,Lodi T,Tigano M.The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency..Am J Hum Genet2009;84:594-604 PMCID:PMC2681006

[78] Ceh-Pavia E,Spiller MP.The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction..Biochem J2014;464:449-59

[79] Daithanka VN,Dong M,Thorpe C.Structure of the human sulfhydryl oxidase augmenter of liver regeneration and characterization of a human mutation causing an autosomal recessive myopathy..Biochemistry2010;49:6737-45 PMCID:PMC2914844

[80] Calderwood L,Teot LA.Adrenal insufficiency in mitochondrial disease: a rare case of GFER-related mitochondrial encephalomyopathy and review of the literature..J Child Neurol2016;31:190-4

[81] Nambot S,Thevenon J.Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data..Clin Genet2017;92:188-98

[82] Stehling O,Lill R.Mitochondrial iron-sulfur protein biogenesis and human disease..Biochimie2014;100:61-77

[83] Hanukoglu I.Mitochondrial cytochrome P-450scc. Mechanism of electron transport by adrenodoxin..J Biol Chem1980;255:3057-61

[84] Paul A,Petit F.FDXR mutations cause sensorial neuropathies and expand the spectrum of mitochondrial fe-s-synthesis diseases..Am J Hum Genet2017;101:630-7 PMCID:PMC5630197

[85] Peng Y,Valencia AC.Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy..Human Molecular Genetics2017;26:4937-50 PMCID:PMC5886230

[86] Slone J,Chamberlin A.Biallelic mutations in FDXR cause neurodegeneration associated with inflammation..J Hum Genet2018;63:1211-22 PMCID:PMC6451867

[87] Brandt U.Energy converting NADH: quinone oxidoreductase (complex I)..Annu Rev Biochem2006;75:69-92

[88] Scheulke M,Mariman E,Plecko B.Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy..Nat Genet1999;21:260-1

[89] Bénit P,Kadhom N,Cormier-Daire V.Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency..Am J Hum Genet2001;68:1344-52 PMCID:PMC1226121

[90] Bindu PS,Chiplunkar S.Mitochondrial leukoencephalopathies: a border zone between acquired and inherited white matter disorders in children?.Mult Scler Relat Disord2018;20:84-92

[91] Björkman K,Darin N,GKollberg G.Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1..Mitochondrion2015;21:33-40

[92] Breningstall GN,Patterson RJ.Siblings with leukoencephalopathy..Semin Pediatr Neurol2008;15:212-5

[93] Bugiani M,Alberio S,Lamantea E.Clinical and molecular findings in children with complex I deficiency..Biochim Biophys Acta2004;1659:136-47

[94] Dinwiddie DL,Miller NA,Farrow EG.Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome..Genomics2013;102:148-56 PMCID:PMC4557607

[95] Incecik F,Besen S.Late-onset leigh syndrome due to NDUFV1 mutation in a 10-year-old boy initially presenting with ataxia..J Pediatr Neurosci2018;13:205-7 PMCID:PMC6057190

[96] Koene S,Van der Knaap MS,Sperl W.Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases..J Inherit Metab Dis2012;35:737-47 PMCID:PMC3432203

[97] Lal D,Motameny S,Thiele H.Homozygous missense mutation of NDUFV1 as the cause of infantile bilateral striatal necrosis..Neurogenetics2013;14:85-7

[98] Laugel V,Cormier-Daire V,de Saint-Martin A.Early-onset ophthalmoplegia in Leigh-like syndrome due to NDUFV1 mutations..Pediatr Neurol2007;36:54-7

[99] Lee JS,Lee M,Jeon E.Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes..Clin Genet2020;97:586-94

[100] Lieber DS,Shanahan K,Liu S.Targeted exome sequencing of suspected mitochondrial disorders..Neurology2013;80:1762-70 PMCID:PMC3719425

[101] Marin SE,Robinson B,Smeitink J.Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2..Gene2013;516:162-7

[102] Moran M,Sanchez-Arago M,Merinero B.Mitochondrial bioenergetics and dynamics interplay in complex I-deficient fibroblasts..Biochim Biophys Acta2010;1802:443-53

[103] Nafisinia M,Dang X,Chen Y.Whole exome sequencing identifies the genetic basis of late-onset leigh syndrome in a patient with MRI but little biochemical evidence of a mitochondrial disorder..JIMD Rep2017;32:117-24 PMCID:PMC5362551

[104] Ortega-Recalde O,Patino LC,Rivera-Nieto C.A novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations..Mitochondrion2013;13:749-54

[105] Pronicka E,Ciara E,Rokicki D.New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre..J Transl Me2016;14:174 PMCID:PMC4903158

[106] Rubio-Gozalbo ME,Wendel U,Trijbels JM.Systemic infantile complex I deficiency with fatal outcome in two brothers..Neuropediatrics1998;29:43-5

[107] Vilain C,Abey A,Van Bogaert P.A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome..Clin Genet2012;82:264-70

[108] Zafeiriou DI,Scheffer H,Pouwels PJW.MR spectroscopy and serial magnetic resonance imaging in a patient with mitochondrial cystic leukoencephalopathy due to complex I deficiency and NDUFV1 mutations and mild clinical course..Neuropediatrics2008;39:172-5

[109] Zhang J,Zhang Z,Kong W.Genotypic spectrum and natural history of cavitating leukoencephalopathies in childhood..Pediatr Neurol2019;94:38-47

[110] Loeffen JL,Trijbels JM,Triepels RH.Isolated complex I deficiency in children: clinical, biochemical, and genetic aspects..Hum Mutat2000;15:123-34

[111] Bénit P,Kadhom N,De Lonlay-Debeney P.Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy..Hum Mutat2003;21:582-6

[112] Pagniez-Mammeri H,Brivet M,Landrieu P.Rapid screening for nuclear genes mutations in isolated respiratory chain complex I defects..Mol Genet Metab2009;96:196-200

[113] Cameron JM,Feigenbaum A,Blaseret S.Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome..Eur J Paediatr Neurol2015;19:525-32

[114] Liu HY,Chuang KT.Mitochondrial targeting of human NADH dehydrogenase (ubiquinone) flavoprotein 2 (NDUFV2) and its association with early-onset hypertrophic cardiomyopathy and encephalopathy..J Biomed Sci2011;18:29 PMCID:PMC3117770

[115] Aldera AP.Gene of the month: SDH..J Clin Pathol2018;7:95-7

[116] Evenepoel L,Krol N,de Krijger RR.Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations..Genet Med2015;17:610-20

[117] Bausch B,Ni Y,Patocs A.Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention..JAMA Oncol2017;3:1204-12 PMCID:PMC5824290

[118] Burnichon N,Libe R,Rivière J.SDHA is a tumor suppressor gene causing paraganglioma..Hum Mol Genet2010;19:3011-20 PMCID:PMC2901140

[119] Dwight T,Benn DE,McKelvie P.Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma..J Clin Endocrinol Metab2013;98:E1103-8

[120] Gill AJ.Succinate dehydrogenase (SDH)-deficient neoplasia..Histopathology2018;72:106-16

[121] Ozluk Y,Matosi A,Berker NK.Renal carcinoma associated with a novel succinate dehydrogenase A mutation: a case report and review of literature of a rare subtype of renal carcinoma..Hum Pathol2015;46:1951-5

[122] Burgeois M,Chretien D,Munnich A.Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome..Brain Dev1992;14:404-8

[123] Bourgeron T,Chretien D,Bourgeois M.Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency..Nat Genet1995;11:144-9

[124] Alston CL,Meloni F,He L.Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency..J Med Genet2012;49:569-77 PMCID:PMC3500770

[125] Helman G,Whitehead MT,Brockmann K.Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy..Ann Neurol2016;79:379-86 PMCID:PMC5712845

[126] Horvath R,Holinski-Feder E,Gempel K.Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA)..J Neurol Neurosurg Psychiatry2006;77:74-6 PMCID:PMC2117401

[127] Ma YY,Liu YP,Li XY.Two compound frame-shift mutations in succinate dehydrogenase gene of a Chinese boy with encephalopathy..Brain Dev2014;36:394-8

[128] Renkema GH,Smeets RJ,Antoine M.SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors..Eur J Hum Genet2015;23:202-9 PMCID:PMC4297908

[129] Van Coster R,Smet J,Gerlo E.Homozygous Gly555Glu mutation in the nuclear encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II..Am J Med Genet A2003;120A:13-8

[130] Pagnamenta AT,Duncan AJ,Heales SJ.Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II..Mol Genet Metab2006;89:214-21

[131] Parfait B,Rotig A,Munnich A.Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome..Hum Genet2000;106:236-43

[132] Levitas A,Harel G,Caspi VC.Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase..Eur J Hum Genet2010;18:1160-5 PMCID:PMC2987458

[133] Taylor RW,Schaefer J,Shakir R.Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia..Ann Neurol1996;39:224-32

[134] Birch-Machin MA,Cochran B,Turnbull DM.Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene..Ann Neurol2000;48:330-5

[135] Courage C,Hahn D,Nuoffer JM.SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement..Am J Med Genet A2017;173:225-30

[136] Olsen RK,Christensen E,Skovby F.Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency..Hum Mutat2003;22:12-23

[137] Frerman FE, Goodman SI. The Metabolic and Molecular Bases of Inherited Disease. In: Scriver CR, Sly WS, Childs B, Beaudet AL, Valle D, Kinzler KW, Vogelstein B, editors. 2001. Defects of Electron Transfer Flavoprotein and Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase: Glutaric Acidemia Type II. Available from: https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225088261. [Last accessed on 27 Jul 2020]

[138] Grünert SC.Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme dehydrogenase deficiency..Orphanet J Rare Dis2014;9:117 PMCID:PMC4222585

[139] Morris AAM.Saudubray JM,Walter JH.Disorders of mitochondrial fatty acid oxidation and Related Metabolic Pathways..Inborn metabolic diseases: diagnosis and treatment.2016;BerlinSpringer

[140] Horvath R.Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ10)..J Inherit Metab Dis2012;35:679-87

[141] Cornelius N,Gregersen N.Cellular consequences of oxidative stress in riboflavin responsive multiple acyl-CoA dehydrogenation deficiency patient fibroblasts..Hum Mol Genet2014;23:4285-301

[142] Cameron JM,Mackay N,Renaud DL.Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins with borderline normal PDH complex activity..Am J Med Genet A2015;140:1542-52

[143] Quinonez SC, Thoene JG. Dihydrolipoamide dehydrogenase deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. 2014. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK220444/. [Last accessed on 27 Jul 2020]

[144] De Meirleir LJ,Brivet M.Saudubray JM,Walter J.Disorders of pyruvate metabolism and the tricarboxylic acid cycle. Inborn metabolic diseases: diagnosis and treatment..2016;BerlinSpringer161-74

[145] Quintana E,Font A,Tort F.Dihydrolipoamide dehydrogenase (DLD) deficiency in a Spanish patient with myopathic presentation due to a new mutation in the interface domain..J Inherit Metab Dis2010;33:S315-9

[146] Carrozzo R,Fiermonte G,Nottia MD.Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency. The chaperon-like effect of vitamin B2..Mitochondrion2014;18:49-57

[147] Tiranti V,Hildebrandt T,Mineri R.Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy..Nat Med2009;15:200-5

[148] Di Meo I,Tiranti V.Adam MP,Pagon RA,Bean LJH,Amemiya A.Ethylmalonic encephalopathy..GeneReviews [Internet] 2017.1993-2018;Seattle (WA)University of Washington

[149] Kožich V,Sokolová J,Krijt J.Metabolism of sulfur compounds in homocystinurias..Br J Pharmacol2019;176:594-606 PMCID:PMC6346072

[150] Viscomi C,Dweikat I,Lamperti C.Combined treatment with oral metronidazole and N-ace-tylcysteine is effective in ethylmalonic encephalopathy..Nat Med2010;16:869-71

[151] Di Meo I,Tiranti V.Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches..EMBO Mol Med2015;7:1257-66 PMCID:PMC4604682

[152] Yoon HR,Ahn YM,Shin YJ.Therapeutic trial in the first three Asian cases of ethylmalonic encephalopathy: response to riboflavin..J Inherit Metab Dis2001;24:870-3

[153] Susin SA,Zamzami N,Snow BE.Molecular characterization of mitochondrial apoptosis-inducing factor..Nature1999;397:441e6

[154] Joza N,Hangen E,Modjtahedi N.AIF: not just an apoptosis-inducing factor..Ann NY Acad Sci2009;1171:2-11

[155] Ghezzi D,Invernizzi F,Mora M.Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor..Am J Hum Genet2010;86:639-49 PMCID:PMC2850437

[156] Berger I,Dor-Wolman T,Saada A.Early prenatal ventriculomegaly due to an aifm1 mutation identified by linkage analysis and whole exome sequencing..Mol Genet Metab2011;104:517-20

[157] Rinaldi C,Sevrioukova IF,Horkayne-Szakaly I.Cowchock syndrome is associated with a mutation in apoptosis-inducing factor..Am J Hum Genet2012;91:1095-102 PMCID:PMC3516602

[158] Zong L,Ealy M,Wang D.Mutations in apoptosis-inducing factor cause x-linked recessive auditory neuropathy spectrum disorder..J Med Genet2015;52:523-31 PMCID:PMC4518735

[159] Mierzewska H,Bieganski T,Mierzewska-Schmidt M.Spondyloepimetaphyseal dysplasia with neurodegeneration associated with aifm1 mutation - a novel phenotype of the mitochondrial disease..Clin Genet2017;91:30-7

[160] Heimer G,Zhu X,Marek-Yagel D.Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin..Eur J Paediatr Neurol2018;22:93-101