Succinate Dehydrogenase: Biogenesis and Role in Disease

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DESCRIPTION (provided by applicant): Succinate dehydrogenase (SDH) is an integral component of the mitochondrial respiratory chain and tricarboxylic acid cycle. The enzyme, containing four subunits and a myriad of redox cofactors, requires assembly factors to facilitate protein assembly and cofactor insertion. We propose to uncover the molecular function of three novel assembly factors required for the formation of active SDH. Mechanistic biochemistry and genetics in yeast are followed by studies in cultured mammalian cells to provide a comprehensive picture of the function of SDH assembly factors. Preliminary studies indicate that Sdh6 (SDHAF1) and Acn9 perform non-redundant functions related to the maturation of the iron-sulfur cluster subunit Sdh2 of SDH. Proposed studies will test whether these two factors facilitate transfer of iron-sulfur clusters to Sdh2, chaperone holo - Sdh2 into the mature tetrameric enzyme or mediate repair of damaged iron-sulfur clusters. Preliminary studies on the third assembly factor Sdh8 showed a role in the assembly of the catalytic Sdh1 subunit. Studies outlined in the proposal will elucidate the nature and function of the Sdh8/Sdh1 complex in the assembly of SDH. We also propose to explore the roles of mutations or dysregulation of these factors in human SDH deficiency disorders. Disorders arising from impaired assembly of SDH result in a variety of pathologies, including leukoencephalopathy, Leigh syndrome, cerebellar atrophy and tumorigenesis. We seek to uncover strongly predicted associations of these novel assembly factors with human SDH-deficiency diseases. We hypothesize that additional SDH assembly factors remain to be discovered, some of which may be susceptibility genes for these previously idiopathic SDH-deficient diseases.