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.

Disease-causing SDHAF1 mutations impair transfer of Fe-S clusters to SDHB / N. Maio, D. Ghezzi, D. Verrigni, T. Rizza, E. Bertini, D. Martinelli, M. Zeviani, A. Singh, R. Carrozzo, T.A. Rouault. - In: CELL METABOLISM. - ISSN 1550-4131. - 23:2(2016 Feb 09), pp. 292-302. [10.1016/j.cmet.2015.12.005]

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

D. Ghezzi
Secondo
;
2016

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.
amino acid motifs; amino acid sequence; Electron Transport Complex II; female; HEK293 cells; humans; hypoxia-inducible factor 1, alpha subunit; infant; infant, newborn; iron-sulfur proteins; leukoencephalopathies; molecular chaperones; molecular sequence data; mutation; protein binding; proteins; riboflavin; succinate dehydrogenase; succinates; physiology; molecular biology; cell biology
Settore MED/03 - Genetica Medica
Settore BIO/11 - Biologia Molecolare
9-feb-2016
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/523741
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