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Mitochondrial succinyl CoA management at the intersection of heme and ketone metabolism

Award Number: F32HL176113
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Mitochondrial succinyl CoA management at the intersection of heme and ketone metabolism - ABSTRACT The objective of this proposal is to determine how cardiac and skeletal muscle myocytes, mitochondrially dense and highly oxidative cells, manage succinyl-CoA (SucCoA). SucCoA serves three conditionally essential metabolic fates: forward tricarboxylic acid cycle (TCAC) flux, heme synthesis, and ketone oxidation. Indeed, sucCoA is a limiting metabolite for the rate-determining enzymes in heme synthesis and ketone oxidation, Delta-aminolevulinate synthase 1 (ALAS1) and Succinyl-CoA:3-ketoacid CoA transferase (SCOT), respectively. In myocytes ketones are a major fasting energy source and heme is the primary oxygen carrier in the form of myoglobin. Heme is also a cofactor for multiple proteins, including several in the electron transport system, rendering it essential for mitochondrial biogenesis. We identified a nutrient dependent reciprocal regulation of ALAS1 and SCOT, that we hypothesize serves to prevent dual pulls on the sucCoA pool. Interestingly, this regulation is lost in heart failure (HF) and sucCoA is depleted. HF is a disease characterized by a progressive deterioration in cardiac pumping capacity concomitant with alterations to oxidative metabolism, including a stark increase in reliance on ketone oxidation at the level of SCOT and β- hydroxybutyrate dehydrogenase 1 (BDH1). While increased ketone oxidation is an emerging hallmark of HF, far less is known regarding heme or the intersection of heme and ketone metabolism in HF. We hypothesize that the unique demands of hypertrophic and failing hearts, which grow increasingly dependent on both ketone oxidation and heme biosynthesis, result in a dual pull on the sucCoA pool, thereby limiting substrate flux through both SCOT and ALAS1. In accordance, we propose two aims to test our hypotheses that: 1) sucCoA availability for heme biosynthesis in myocytes depends on carbon source, nutritional status, and ALAS1 interactome, and 2) that sucCoA availability limits heme synthesis and mitochondrial biogenesis in hypertrophied and failing hearts. To test this model, we will combine state-of-the-art molecular profiling tools, Langendorff perfused hearts, and metabolic flux analysis with stable isotope tracers, ultimately filling fundamental gaps in knowledge of myocyte heme biology and furthering our understanding of HF pathophysiology. These studies will employ primary human myocytes for flux and interactome analysis and a novel myocyte specific double SCOT and BDH1 knockout mouse (MCK-DKO). The training environment at DMPI is uniquely suited to support these studies due to its robust core facilities and trainee support. In fulfilling the aims proposed herein, the applicant will simultaneously expand their technical skillset and integrate their computational and basic science skills. This supports the applicant’s long-term goal of becoming an academic investigator. The proposed work will expand our fundamental understanding of heme biology and cardiovascular physiology, ultimately contributing to new therapeutic approaches for HF.


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: 2026 ( Subtotal = $78,052 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	000	2	3/25/2026	NON-COMPETING CONTINUATION	$78,052
														Subtotal = $78,052

Issue Date FY: 2024 ( Subtotal = $73,408 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	000	1	8/1/2024	NEW	$73,408
														Subtotal = $73,408

Grand Total All Awards = $151,460

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Mitochondrial succinyl CoA management at the intersection of heme and ketone metabolism

Award Number: F32HL176113

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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