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. Epub 2015 Dec 31.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Leukoencephalopathies / pathology
  • Molecular Chaperones / metabolism
  • Molecular Sequence Data
  • Mutation / genetics*
  • Protein Binding / drug effects
  • Proteins / chemistry
  • Proteins / genetics*
  • Riboflavin / pharmacology
  • Succinate Dehydrogenase / chemistry
  • Succinate Dehydrogenase / metabolism*
  • Succinates / metabolism


  • 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