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THE MITOCHONDRIAL DYNAMISM/FITNESS/BIOGENESIS INTERACTOME IN CARDIAC DISEASE

Award Number: R35HL135736
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/16/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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THE MITOCHONDRIAL DYNAMISM/FITNESS/BIOGENESIS INTERACTOME IN CARDIAC DISEASE - The mitochondrial dynamism/fitness/biogenesis interactome in cardiac disease Dorn GW II Abstract Cardiomyocyte mitochondria are essential providers of ATP that fuels contraction and normal or reparative cardiomyocyte growth. Observationally, cardiomyocyte utilization of metabolic substrates evolves during cardiac development from a fetal preference for carbohydrates to the normal adult preference for fatty acids. In adult hearts, pathological reversion toward mitochondrial utilization of carbohydrates is postulated to contribute to cardiac hypertrophy, heart failure and myocardial infarction. However, our grasp of specific mechanisms that direct cardiac substrate utilization is incomplete, and forced genetic production of cardiomyocyte mitochondria has not proven therapeutic in experimental models of heart disease. Our conceptual breakthrough was that cardiac metabolism is not determined by a “master regulator”, but is directed by the interplay between mitochondrial dynamism, fitness and biogenesis. We posit that myocardial metabolic remodeling requires coordinated modulation of mitophagic mitochondrial removal, biogenic mitochondrial replacement and fusion/fission-mediated mitochondrial redistribution. By individually disrupting these pathways and defining the consequences on mitochondrial, cell and organ functioning we determined how these three processes are co-regulated and functionally-interdependent, therein defining a central role for Mfn2 as orchestrator of mitochondrial fate (i.e. retention vs removal). By engineering artificial Mfn2 mutations and studying damaging human Mfn2 mutations identified through DNA sequencing of cardiomyopathy cohorts we are learning how each major process within the interactome is internally fine-tuned through modulation of functionally opposing pairs. Specifically, Mfn-mediated mitochondrial fusion is opposed by Drp1- mediated mitochondrial fission; PGC1-mediated biogenesis of fatty acid-catabolizing mitochondria is opposed by PRC-mediated biogenesis of carbohydrate-catabolizing mitochondria; and mitochondrial replication is opposed by Parkin-mediated mitochondrial elimination. Based on these insights, which represent a convergence of the research aims of HL59888 (mito fusion) and HL128441 (mitophagy), we developed novel genetic and biochemical tools, namely Separation-of-Function mutant Mfn2 proteins and cell-permeant peptides, to specifically manipulate mitochondrial dynamism or mitophagy in vitro and in vivo. We will employ these new concepts and reagents to dissect the molecular mechanisms that drive metabolic remodeling in normal and diseased hearts, and to develop translatable means of optimally matching cardiac metabolism to pathophysiological status by “dialing- in” mitochondrial quality and quantity via precision manipulations within the interactome.


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: 2024 ( Subtotal = -$284,077 )
2024	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	7	4/19/2024	NON-COMPETING CONTINUATION	-$284,077
														Subtotal = -$284,077

Issue Date FY: 2023 ( Subtotal = $915,000 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	001	7	3/3/2023	NON-COMPETING CONTINUATION	$91,500
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	7	12/8/2022	NON-COMPETING CONTINUATION	$823,500
														Subtotal = $915,000

Issue Date FY: 2022 ( Subtotal = $915,000 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	6	11/19/2021	NON-COMPETING CONTINUATION	$823,500
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	001	6	6/8/2022	NON-COMPETING CONTINUATION	$91,500
														Subtotal = $915,000

Issue Date FY: 2021 ( Subtotal = $915,000 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	5	12/24/2020	NON-COMPETING CONTINUATION	$823,500
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	001	5	5/15/2021	NON-COMPETING CONTINUATION	$91,500
														Subtotal = $915,000

Issue Date FY: 2020 ( Subtotal = $915,000 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	4	12/18/2019	NON-COMPETING CONTINUATION	$869,250
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	001	4	3/13/2020	NON-COMPETING CONTINUATION	$45,750
														Subtotal = $915,000

Issue Date FY: 2019 ( Subtotal = $915,000 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	3	12/21/2018	NON-COMPETING CONTINUATION	$915,000
														Subtotal = $915,000

Issue Date FY: 2018 ( Subtotal = $915,000 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	2	1/11/2018	NON-COMPETING CONTINUATION	$896,700
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	001	2	7/7/2018	NON-COMPETING CONTINUATION	$18,300
														Subtotal = $915,000

Issue Date FY: 2017 ( Subtotal = $915,000 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	1	1/16/2017	NEW	$915,000
														Subtotal = $915,000

Grand Total All Awards = $6,120,923

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THE MITOCHONDRIAL DYNAMISM/FITNESS/BIOGENESIS INTERACTOME IN CARDIAC DISEASE

Award Number: R35HL135736

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/16/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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