TY - JOUR
T1 - Disease-causing SDHAF1 mutations impair transfer of Fe-S clusters to SDHB
AU - Maio, Nunziata
AU - Ghezzi, Daniele
AU - Verrigni, Daniela
AU - Rizza, Teresa
AU - Bertini, Enrico Silvio
AU - Martinelli, Diego
AU - Zeviani, Massimo
AU - Singh, Anamika
AU - Carrozzo, Rosalba
AU - Rouault, Tracey A.
PY - 2016/2/9
Y1 - 2016/2/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2015.12.005
DO - 10.1016/j.cmet.2015.12.005
M3 - Article
VL - 23
SP - 292
EP - 302
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 2
ER -