The LYR Factors SDHAF1 and SDHAF3 Mediate Maturation of the Iron-Sulfur Subunit of Succinate Dehydrogenase

Abstract

Summary 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.

Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease

“…These include ISD11, the obligate NFS1-binding partner [107], SDHAF1 and SDHAF3, the latter two of which were recently shown to be involved in mediating the maturation of the SDHB [108]. Additionally, Winge"s group has also shown that the LYRM protein, Mzm1, functions in the insertion and/or stabilization of the ISC-containing subunit of complex III [109].…”

Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB

“…Furthermore, SDHAF1 interacts with the C-terminus of SDHB, raising the possibility that it participates in biogenesis of the SDH complex by providing nascent Fe-S clusters to SDHB (Maio et al, 2014). Previous studies in S. cerevisiae concluded that Sdh6, the SDHAF1 ortholog, exerts its function on SDH assembly by binding to and protecting an Sdh1-Sdh2 intermediate (SDHA-SDHB in human, respectively) from the deleterious effects of oxidants (Na et al, 2014). However, the human protein failed to rescue the respiratory defect of a Δ Sdh6 yeast strain (Ghezzi et al, 2009).…”

Synthesis, delivery and regulation of eukaryotic heme and Fe–S cluster cofactors

“…SDHAF2, an assembly protein that flavinates SDH, is also implicated in paragangliomas. Recently, two additional Fe-S assembly proteins, SDHAF1 and SDHAF3, were found to stabilize Fe-S cluster assembly in SDH 190 . The later two proteins have LYR-motifs (Leu-Tyr-Arg) common to proteins involved in Fe-S cluster assembly.…”