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.
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•SDH maturation is dependent on two Sdh2-specific assembly factors•Yeast cells lacking SDHAF1 and SDHAF3 are sensitive to endogenous oxidants•Drosophila lacking SDHAF3 exhibit muscular and neuronal dysfunction
Na et al. show that maturation of the iron-sulfur cluster subunit (sdh2) of mitochondrial succinate dehydrogenase (which links the TCA cycle to the electron transport chain) is dependent on the assembly factors Sdh6 (SDHAF1) and Sdh7 (SDHAF3). These factors shield the sdh2 complex against endogenous oxidants during assembly.
