title: Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB.
abstract: SDHAF1 mutations cause a rare mitochondrial complex II (CII) deficiency, which manifests as infantile leukoencephalopathy with elevated levels of serum and white matter succinate and lactate. Here, we demonstrate that SDHAF1 contributes to iron-sulfur (Fe-S) cluster incorporation into the Fe-S subunit of CII, SDHB. SDHAF1 transiently binds to aromatic peptides of SDHB through an arginine-rich region in its C terminus and specifically engages a Fe-S donor complex, consisting of the scaffold, holo-ISCU, and the co-chaperone-chaperone pair, HSC20-HSPA9, through an LYR motif near its N-terminal domain. Pathogenic mutations of SDHAF1 abrogate binding to SDHB, which impairs biogenesis of holo-SDHB and results in LONP1-mediated degradation of SDHB. Riboflavin treatment was found to ameliorate the neurologic condition of patients. We demonstrate that riboflavin enhances flavinylation of SDHA and reduces levels of succinate and Hypoxia-Inducible Factor (HIF)-1α and -2α, explaining the favorable response of patients to riboflavin.
authors.affiliation: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 9000 Rockville Pike, 20892, Bethesda, MD, USA.
authors.forename: Nunziata
authors.initials: N
authors.lastname: Maio
authors.affiliation: Unit of Molecular Neurogenetics, Foundation Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carattere Scientifico, 20126 Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.affiliation: Unit for Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Verrigni
authors.affiliation: Unit for Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rizza
authors.affiliation: Unit for Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Unit of Metabolism, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 9000 Rockville Pike, 20892, Bethesda, MD, USA.
authors.forename: Anamika
authors.initials: A
authors.lastname: Singh
authors.affiliation: Unit for Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.affiliation: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 9000 Rockville Pike, 20892, Bethesda, MD, USA. Electronic address: rouault@mail.nih.gov.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Rouault
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D042963:Electron Transport Complex II / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D056784:Leukoencephalopathies / Q000235:genetics* / Q000473:pathology; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D012256:Riboflavin / Q000494:pharmacology; D013385:Succinate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D013386:Succinates / Q000378:metabolism
chemical_list: C490651:HSCB protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007506:Iron-Sulfur Proteins; D018832:Molecular Chaperones; D011506:Proteins; C553227:SDHAF1 protein, human; D013386:Succinates; D042963:Electron Transport Complex II; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D012256:Riboflavin