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Departmental Seminar: Dr. Dennis Winge
Event Date: 10.14.2013
Day: Monday
Time: 12:00 pm
Location: 700 Fairchild
Event Type: Departmental


Departments of Biochemistry and Internal Medicine
University of Utah Health Sciences Center

Title: " Assembly of Succinate Dehydrogenase: Interplay Between Iron-Sulfur Cofactor Insertion and Subunit Assembly"



Succinate dehydrogenase (SDH) is an integral component of the mitochondrial respiratory chain that catalyzes the oxidation of succinate to fumarate. The tetrameric enzyme contains 5 redox cofactors including a covalently bound FAD and 3 FeS clusters in a hydrophilic segment consisting of Sdh1 and Sdh2 subunits and a membrane anchor domain consisting of the other two subunits. The biogenesis of SDH is dependent on assembly factors for the insertion of redox cofactors. Covalent addition of FAD in the Sdh1 subunit is facilitated by the (SDHAF2) assembly factor. Two novel assembly factors Sdh6 (SDHAF1) and Acn9 facilitate the maturation of Sdh2, which includes the insertion of three FeS clusters (2Fe-2S, 4Fe-4S and 3Fe-4S centers). Yeast lacking either Sdh6 or Acn9 are partially impaired in the maturation of Sdh2, but a marked impairment is seen in a double mutant strain. The dependency of SDH assembly on the Sdh6 and Acn9 factors is especially marked in respiratory cultures. The mutant cells exhibit a marked instability in the FeS subunit Sdh2. In cells lacking the membrane anchor subunits, Sdh6 and Acn9 associate with the two catalytic subunits Sdh1 and Sdh2 in an assembly intermediate. Genetic suppressors of the respiratory defect of cells lacking either Sdh6 or Acn9 were recovered and identified as Yap1, which activates the expression of anti-oxidant genes. The SDH defect seen in sdh6 or acn9 mutant cells is reversed by exogenous antioxidants. We propose that Sdh6 and Acn9 function as Sdh2 chaperones stabilizing the subunit during the insertion of the three FeS clusters. Sdh6 and Acn9 appear to protect the Sdh2 against endogenous oxidants during FeS cluster insertion and prior to its association with the membrane anchor subunits associate to form the holo-enzyme. The human Sdh6 ortholog SDHAF1 has a conserved function in chaperoning the FeS subunit during SDH biogenesis.

Host: Dr. Alex Tzagoloff