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.

Public Health Relevance

We propose to uncover the molecular function of the three novel assembly factors required for the formation of mitochondrial succinate dehydrogenase (SDH). 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM110755-04
Application #
9221347
Study Section
Special Emphasis Panel (ZRG1-EMNR-T (02)M)
Program Officer
Anderson, Vernon
Project Start
2014-05-01
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
4
Fiscal Year
2017
Total Cost
$234,822
Indirect Cost
$77,223
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Van Vranken, Jonathan G; Nowinski, Sara M; Clowers, Katie J et al. (2018) ACP Acylation Is an Acetyl-CoA-Dependent Modification Required for Electron Transport Chain Assembly. Mol Cell 71:567-580.e4
Tanner, Jason M; Bensard, Claire; Wei, Peng et al. (2017) EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma. Mol Cancer Res 15:1517-1530
Fetherolf, Morgan M; Boyd, Stefanie D; Taylor, Alexander B et al. (2017) Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site. J Biol Chem 292:12025-12040
Schell, John C; Wisidagama, Dona R; Bensard, Claire et al. (2017) Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol 19:1027-1036
Dwight, Trisha; Na, Un; Kim, Edward et al. (2017) Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma. BMC Cancer 17:497
Cory, Seth A; Van Vranken, Jonathan G; Brignole, Edward J et al. (2017) Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. Proc Natl Acad Sci U S A 114:E5325-E5334
Melber, Andrew; Na, Un; Vashisht, Ajay et al. (2016) Role of Nfu1 and Bol3 in iron-sulfur cluster transfer to mitochondrial clients. Elife 5:
Melber, Andrew; Winge, Dennis R (2016) Inner Secrets of the Respirasome. Cell 167:1450-1452
Kim, Hyung J; Jeong, Mi-Young; Parnell, Timothy J et al. (2016) The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria. J Biol Chem 291:17417-26
Van Vranken, Jonathan G; Jeong, Mi-Young; Wei, Peng et al. (2016) The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis. Elife 5:

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