Journal
CELL METABOLISM
Volume 23, Issue 2, Pages 292-302Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.12.005
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Funding
- Eunice Kennedy Shriver NICHD Intramural Research Program
- Cell lines and DNA Bank of Paediatric Movement Disorders and Neurodegenerative Diseases of the Telethon Network of Genetic Biobanks [GTB12001J]
- EurobiobanK Network
- Pierfranco and Luisa Mariani Foundation
- Telethon [GGP11011]
- ERC [FP7-322424]
- MRC [MC_UP_1002/1] Funding Source: UKRI
- Medical Research Council [MC_UP_1002/1] Funding Source: researchfish
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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)-1 alpha and -2 alpha, explaining the favorable response of patients to riboflavin.
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