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: Nunziata Maio, Daniele Ghezzi, Daniela Verrigni, Teresa Rizza, Enrico Bertini, Diego Martinelli, Massimo Zeviani, Anamika Singh, Rosalba Carrozzo, Tracey A Rouault
• Journal: Cell metabolism (Cell Metab) Vol. 23 Issue 2 Pg. 292-302 (Feb 09 2016) ISSN: 1932-7420 [Electronic] United States
• PMID: 26749241 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• HSCB protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Iron-Sulfur Proteins
• Molecular Chaperones
• Proteins
• SDHAF1 protein, human
• Succinates
• Electron Transport Complex II
• SDHB protein, human
• Succinate Dehydrogenase
• Riboflavin

Topics

• Amino Acid Motifs
• Amino Acid Sequence
• Electron Transport Complex II (metabolism)
• Female
• HEK293 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Infant
• Infant, Newborn
• Iron-Sulfur Proteins (metabolism)
• Leukoencephalopathies (genetics, pathology)
• Molecular Chaperones (metabolism)
• Molecular Sequence Data
• Mutation (genetics)
• Protein Binding (drug effects)
• Proteins (chemistry, genetics)
• Riboflavin (pharmacology)
• Succinate Dehydrogenase (chemistry, metabolism)
• Succinates (metabolism)