Disease-causing SDHAF1 mutations impair transfer of Fe-S clusters to SDHB

Nunziata Maio, Daniele Ghezzi, Daniela Verrigni, Teresa Rizza, Enrico Bertini, Diego Martinelli, Massimo Zeviani, Anamika Singh, Rosalba Carrozzo, Tracey A. Rouault

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)292-302
Number of pages11
JournalCell Metabolism
Issue number2
Publication statusPublished - Feb 9 2016

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology


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