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Cell Metab. 2014 Aug 5;20(2):253-66. doi: 10.1016/j.cmet.2014.05.014. Epub 2014 Jun 19.

The LYR factors SDHAF1 and SDHAF3 mediate maturation of the iron-sulfur subunit of succinate dehydrogenase.

Author information

1
Department of Medicine, University of Utah Health Sciences Center 5C426 School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132-2408, USA; Department of Biochemistry, University of Utah, 15 North Medical Drive East, Salt Lake City, UT 84112-5650, USA.
2
Department of Human Genetics, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112-5330, USA.
3
Department of Biochemistry, University of Utah, 15 North Medical Drive East, Salt Lake City, UT 84112-5650, USA.
4
Departments of Pediatrics and Pediatric Neurology, Faculty of Medicine, University of Göttingen, Robert Koch Strasse 40, 37075 Göttingen, Germany.
5
Department of Medicine, University of Utah Health Sciences Center 5C426 School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132-2408, USA; Department of Biochemistry, University of Utah, 15 North Medical Drive East, Salt Lake City, UT 84112-5650, USA. Electronic address: dennis.winge@hsc.utah.edu.

Abstract

Disorders arising from impaired assembly of succinate dehydrogenase (SDH) result in a myriad of pathologies, consistent with its unique role in linking the citric acid cycle and electron transport chain. In spite of this critical function, however, only a few factors are known to be required for SDH assembly and function. We show here that two factors, Sdh6 (SDHAF1) and Sdh7 (SDHAF3), mediate maturation of the FeS cluster SDH subunit (Sdh2/SDHB). Yeast and Drosophila lacking SDHAF3 are impaired in SDH activity with reduced levels of Sdh2. Drosophila lacking the Sdh7 ortholog SDHAF3 are hypersensitive to oxidative stress and exhibit muscular and neuronal dysfunction. Yeast studies revealed that Sdh6 and Sdh7 act together to promote Sdh2 maturation by binding to a Sdh1/Sdh2 intermediate, protecting it from the deleterious effects of oxidants. These studies in yeast and Drosophila raise the possibility that SDHAF3 mutations may be associated with idiopathic SDH-associated diseases.

PMID:
24954417
PMCID:
PMC4126850
DOI:
10.1016/j.cmet.2014.05.014
[Indexed for MEDLINE]
Free PMC Article

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