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Changes in Coenzyme A Levels are a Key Mechanism Regulating Metabolic Pathways

Award Number: R35GM119528
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Changes in Coenzyme A Levels are a Key Mechanism Regulating Metabolic Pathways - Project Summary Coenzyme A (CoA) is an essential cofactor and the major acyl group carrier in mammalian cells. CoA plays a central and regulatory role in energy metabolism, as its acyl-CoA derivatives are substrates for hundreds of metabolic reactions and the posttranslational modification of histones and key metabolic enzymes. CoA- dependent processes occur in multiple subcellular compartments, and major pools of CoA are found in the mitochondria, peroxisomes and cytosol. At the whole tissue level, the concentration of CoA is tightly regulated and dynamically adjusted to changes in the metabolic state. The importance of such a tight control over CoA levels is underscored by the fact that genetic manipulations that force the concentration of CoA outside of its homeostatic range result in loss of metabolic regulation and organ function. For example, the inability to increase CoA levels during a fast blunts fatty acid oxidation and gluconeogenesis in the liver, causing fasting hypoglycemia. On the other hand, an abnormally high concentration of CoA in skeletal muscle is associated with decreased muscle mass, ATP levels and exercise performance, highlighting the importance of mechanisms that prevent the accumulation of this cofactor to toxic levels. The concentration of CoA is regulated by balancing its synthesis and degradation. The process of CoA degradation is poorly characterized. Furthermore, the mechanisms that regulate the different subcellular CoA pools are incompletely understood. During the previous funding cycle, we have characterized the biochemical and regulatory properties of two CoA-degrading enzymes, Nudt7 and Nudt19, which reside in liver and kidney peroxisomes, respectively. Our published and unpublished observations support the conclusion that these enzymes regulate peroxisomal lipid metabolism. Furthermore, deletion of Nudt19 leads to the accumulation of 3-hydroxy-3-methylglutaryl-CoA in the kidneys, suggesting a connection to cholesterol synthesis. We also identified the first mammalian CoA-degrading enzyme, Nudt8, which resides in the mitochondria, and we have recently generated Nudt8-/- mice. The existence of CoA- degrading enzymes in both peroxisomes and mitochondria suggests that these enzymes contribute to the regulation of the CoA pools within these organelles. The long-term goal of our research program is to understand the mechanisms that regulate tissue CoA levels and to harness them to manipulate the metabolic network for the treatment or prevention of metabolic disorders. To move toward this goal, we propose to 1) determine the mechanisms through which Nudt19 regulates kidney lipid metabolism and kidney function and 2) determine the role played by Nudt8 in the regulation of the mitochondrial CoA pool and mitochondrial metabolism. This research program will advance our understanding of the mechanisms that regulate the peroxisomal and mitochondrial CoA pools. Furthermore, identifying the processes regulated by each CoA-degrading enzyme will aid in the development of strategies to target and correct specific CoA-dependent pathways in metabolic disorders.


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: 2025 ( Subtotal = $380,000 )
2025	2025	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	001	10	5/22/2025	NON-COMPETING CONTINUATION	$380,000
2025	2024	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	9	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $380,000

Issue Date FY: 2024 ( Subtotal = $468,816 )
2024	2024	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	9	5/10/2024	NON-COMPETING CONTINUATION	$380,000
2024	2024	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	001	9	9/18/2024	SUPPLEMENT FOR EXPANSION	$88,816
														Subtotal = $468,816

Issue Date FY: 2023 ( Subtotal = $504,260 )
2023	2023	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	001	8	6/27/2023	SUPPLEMENT FOR EXPANSION	$124,260
2023	2023	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	8	5/15/2023	NON-COMPETING CONTINUATION	$380,000
														Subtotal = $504,260

Issue Date FY: 2022 ( Subtotal = $395,863 )
2022	2022	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	001	7	6/2/2022	NON-COMPETING CONTINUATION	$380,000
2022	2022	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	002	7	6/7/2022	SUPPLEMENT FOR EXPANSION	$15,863
2022	2020	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	5	4/3/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $395,863

Issue Date FY: 2021 ( Subtotal = $391,560 )
2021	2021	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	6	4/20/2021	COMPETING CONTINUATION	$391,560
														Subtotal = $391,560

Issue Date FY: 2020 ( Subtotal = $375,000 )
2020	2020	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	5	5/14/2020	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2019 ( Subtotal = $375,000 )
2019	2019	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	4	5/20/2019	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2018 ( Subtotal = $375,000 )
2018	2018	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	3	5/22/2018	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2017 ( Subtotal = $375,000 )
2017	2017	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	2	5/19/2017	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2016 ( Subtotal = $356,000 )
2016	2016	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	POB 6001, UNIV SVCS CTR #3038B	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	1	7/14/2016	NEW	$356,000
														Subtotal = $356,000

Grand Total All Awards = $3,996,499

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Changes in Coenzyme A Levels are a Key Mechanism Regulating Metabolic Pathways

Award Number: R35GM119528

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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