Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB

  • Cell Metab. 2016 Feb 9;23(2):292-302. doi: 10.1016/j.cmet.2015.12.005.
Nunziata Maio  1 ,  Daniele Ghezzi  2 ,  Daniela Verrigni  3 ,  Teresa Rizza  3 ,  Enrico Bertini  3 ,  Diego Martinelli  4 ,  Massimo Zeviani  5 ,  Anamika Singh  1 ,  Rosalba Carrozzo  3 ,  Tracey A Rouault  6
Affiliations
  • 1. Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 9000 Rockville Pike, 20892, Bethesda, MD, USA.
  • 2. Unit of Molecular Neurogenetics, Foundation Carlo Besta Neurological Institute, Istituto di Ricovero e Cura a Carattere Scientifico, 20126 Milan, Italy.
  • 3. 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.
  • 4. Unit of Metabolism, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
  • 5. Mitochondrial Biology Unit, Medical Research Council, Hills Road, Cambridge CB2 0XY, UK.
  • 6. Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 9000 Rockville Pike, 20892, Bethesda, MD, USA. Electronic address: [email protected].
PMID: 26749241 DOI: 10.1016/j.cmet.2015.12.005
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.