Wednesday, December 6, 2023 12/6/2023

Structure/Function of Complex II Oxidoreductase

Award Number: R01GM061606
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Mitochondrial Complex II, also known as succinate dehydrogenase (SDH) is a membrane-bound heterotetramer (SDH-ABCD) whose four subunits are encoded by nuclear DNA. Complex II has a dual function in the cell by linking two essential energy-producing processes. As part of the TCA cycle the hydrophilic SDHAB domain oxidizes succinate to fumarate. This oxidation generates electrons that are transferred through the Fe-S clusters of the SDHB subunit to reduce ubiquinone within the SDHCD membrane domain to provide reducing equivalent to the electron transport chain needed for energy generation. As a key metabolic enzyme malfunction of Complex II is associated with debilitating neurodegenerative diseases and tumor formation. Although a significant amount of information is available on the structure and function of mature Complex II, there is gap in our understanding of how the enzyme assembles into a functional complex. In this project we will identify how various assembly factors work together to insert the flavin (FAD) and Fe-S redox centers into the SDHAB subunits and how this process is coordinated to assemble a functional Complex II. Aim 1: Our recent progress has provided insight into how assembly chaperones interact with the bacterial SdhA subunit to form the covalent FAD linkage needed for catalysis. We will expand on these findings to show how substrates enable protein domain movements to activate this assembly process and control catalysis in both bacterial SdhA and human SDHA subunits. This will be accomplished by x-ray crystallography, SAXS, and double electron electron resonance (DEER) spectroscopy of different intermediate assembly states. Aim 2: It is known that the Fe-S containing subunit requires specific assembly factors to incorporate its clusters. In this aim we investigate how the human SDHB (or bacterial SdhB) subunit incorporates its three unique Fe-S clusters localized into two separate protein domains. We also will determine whether the unique Complex II assembly chaperones assist with the insertion of the Fe-S clusters, or whether they stabilize the protein intermediates for interaction with the rest of the cellular Fe-S assembly machinery. Aim 3: Either malfunction of Complex II assembly or disassociation of the assembled complex during ischemia/reperfusion can contribute pathologies in mitochondrial function. In this aim we reveal mechanisms of how the SDHA and SDHB subunits form a functional subcomplex and aberrant activities associated with accumulation of the SDHAB subcomplex. A focus of this aim is how assembly factors and other proteins control the potentially deleterious reactive oxygen species that can be formed from the SDHAB subcomplex.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	20	8/31/2023	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2022 ( Subtotal = $668,306 )
2022	2022	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	20	5/17/2022	NON-COMPETING CONTINUATION	$66,832
2022	2022	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	20	11/22/2021	NON-COMPETING CONTINUATION	$601,474


Issue Date FY: 2021 ( Subtotal = $672,518 )
2021	2021	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	19	3/11/2021	NON-COMPETING CONTINUATION	$67,252
2021	2021	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	19	11/5/2020	NON-COMPETING CONTINUATION	$605,266


Issue Date FY: 2020 ( Subtotal = $672,518 )
2020	2020	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	18	3/6/2020	NON-COMPETING CONTINUATION	$67,252
2020	2020	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	18	11/22/2019	NON-COMPETING CONTINUATION	$605,266


Issue Date FY: 2019 ( Subtotal = $685,845 )
2019	2019	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	003	17	5/13/2019	COMPETING CONTINUATION	$100,796
2019	2019	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	17	1/4/2019	COMPETING CONTINUATION	$685,845
2019	2017	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	16	1/1/2019	NON-COMPETING CONTINUATION	$0
2019	2017	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	002	16	5/13/2019	NON-COMPETING CONTINUATION	-$100,796


Issue Date FY: 2017 ( Subtotal = $631,640 )
2017	2017	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	16	5/10/2017	NON-COMPETING CONTINUATION	$568,476
2017	2017	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	16	6/7/2017	NON-COMPETING CONTINUATION	$63,164


Issue Date FY: 2016 ( Subtotal = $648,005 )
2016	2016	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	15	9/1/2016	SUPPLEMENT FOR EXPANSION	$49,096
2016	2016	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	15	5/11/2016	NON-COMPETING CONTINUATION	$470,921
2016	2016	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	002	15	9/15/2016	SUPPLEMENT FOR EXPANSION	$127,988


Issue Date FY: 2015 ( Subtotal = $470,921 )
2015	2015	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	14	4/28/2015	NON-COMPETING CONTINUATION	$470,921


Issue Date FY: 2014 ( Subtotal = $484,246 )
2014	2014	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	13	7/2/2014	COMPETING CONTINUATION	$484,246
2014	2012	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	12	6/27/2014	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2012 ( Subtotal = $336,123 )
2012	2012	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	12	7/24/2012	NON-COMPETING CONTINUATION	$336,123


Issue Date FY: 2011 ( Subtotal = $336,123 )
2011	2011	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	11	7/26/2011	NON-COMPETING CONTINUATION	$336,123


Issue Date FY: 2010 ( Subtotal = $339,712 )
2010	2010	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	10	7/14/2010	NON-COMPETING CONTINUATION	$339,712


Issue Date FY: 2009 ( Subtotal = $565,741 )
2009	2009	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	9	7/30/2009	COMPETING CONTINUATION	$356,500
2009	2009	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Trans-NIH Recovery Act Research Support	001	9	9/22/2009	SUPPLEMENT FOR EXPANSION	$209,241


Issue Date FY: 2008 ( Subtotal = $332,456 )
2008	2008	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	8	7/21/2008	NON-COMPETING CONTINUATION	$332,456


Issue Date FY: 2007 ( Subtotal = $332,456 )
2007	2007	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	7	8/1/2007	NON-COMPETING CONTINUATION	$332,456


Issue Date FY: 2006 ( Subtotal = $342,385 )
2006	2006	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	6	7/17/2006	NON-COMPETING CONTINUATION	$342,385


Issue Date FY: 2005 ( Subtotal = $350,625 )
2005	2005	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	5	8/1/2005	COMPETING CONTINUATION	$350,625


Issue Date FY: 2004 ( Subtotal = $321,750 )
2004	2004	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	4	6/21/2004	NON-COMPETING CONTINUATION	$321,750


Issue Date FY: 2003 ( Subtotal = $290,550 )
2003	2003	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH & EDUCATION	4150 CLEMENT STREET	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	3	5/26/2003	NON-COMPETING CONTINUATION	$290,550


Issue Date FY: 2002 ( Subtotal = $290,550 ) (Continued on the next page)
Grand Total All Awards = $9,063,020

Sum of Action Amount is $9,063,020;

Grand Total = $9,063,020

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Structure/Function of Complex II Oxidoreductase

Award Number: R01GM061606

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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