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Metabolic Impact and Mechanism of Enhanced Mitochondrial Calcium Uptake in Mitochondrial Cardiomyopathies

Award Number: R01HL141353
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Metabolic Impact and Mechanism of Enhanced Mitochondrial Calcium Uptake in Mitochondrial Cardiomyopathies - PROJECT SUMMARY Diseases that arise from mutations in components of mitochondrial oxidative phosphorylation can be devastating, as mitochondria are crucial for energy synthesis. These diseases occur predominantly in infants and children, with a prevalence of 1 in 5000. Though virtually any organ can be affected, the heart is frequently involved, because cardiac function has such high energy requirements. These mitochondrial cardiomyopathies have a particularly grim prognosis, with mortality rates increased nearly three-fold compared to children without cardiac involvement, and no specific therapies available. In linking cardiac function to mitochondrial metabolism, calcium signaling may be central to the pathological process. Calcium influx into the mitochondria can potently stimulate ATP synthesis. In the initial period of this application, we identified a regulatory mechanism by which dysfunction within Complex I of the electron transport chain causes a compensatory increase in activity of the mitochondrial calcium uniporter channel, preserving ATP synthesis. During normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter, a mechanism we term Complex I-induced protein turnover (CLIPT). During Complex I dysfunction, interaction with the uniporter is inhibited, preventing degradation and leading to a build-up in functional channels. This mechanism is widespread and was seen in fruit flies, mice, and humans. Moreover, while inhibiting the uniporter led to early demise in Complex I-deficient animals, enhancing uniporter stability rescued survival and function. In this project period, we propose the following three aims to further study this pathway and determine whether it can be exploited for potential therapeutic benefit. We focus on mitochondrial one-carbon (1C) metabolism, a producer of mitochondrial antioxidant species (NAPDH), because this pathway is substantially upregulated in mitochondrial cardiomyopathies. In the first aim, we will examine if adenine dinucleotides (NAD+/NADP+) regulate the uniporter, and if calcium regulates critical 1C metabolism enzymes. In the second aim, we will establish whether uniporter activity in mitochondrial cardiomyopathies extends beyond ATP synthesis to NADPH biology, affecting redox balance and one-carbon metabolism. In the third aim, we will test whether manipulation of the portion of the uniporter that interacts with Complex I, the uniporter N-terminal domain (NTD), can be exploited in mouse models as a potential therapy for mitochondrial cardiomyopathies.


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 = $590,741 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	001	8	5/20/2025	NON-COMPETING CONTINUATION	$590,741
2025	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	5	1/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $590,741

Issue Date FY: 2024 ( Subtotal = $578,928 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	7	4/22/2024	NON-COMPETING CONTINUATION	$531,667
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	001	7	6/25/2024	NON-COMPETING CONTINUATION	$47,261
														Subtotal = $578,928

Issue Date FY: 2023 ( Subtotal = $604,241 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	001	6	7/10/2023	COMPETING CONTINUATION	$604,241
2023	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	5	7/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $604,241

Issue Date FY: 2022 ( Subtotal = $381,250 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	001	5	6/29/2022	NON-COMPETING CONTINUATION	$38,125
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	5	4/16/2022	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $381,250

Issue Date FY: 2021 ( Subtotal = $381,250 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	4	4/10/2021	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2020 ( Subtotal = $381,250 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	3	4/1/2020	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2019 ( Subtotal = $381,250 )
2019	2019	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	2	4/11/2019	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2018 ( Subtotal = $380,834 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	1	5/14/2018	NEW	$380,834
														Subtotal = $380,834

Grand Total All Awards = $3,679,744

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Metabolic Impact and Mechanism of Enhanced Mitochondrial Calcium Uptake in Mitochondrial Cardiomyopathies

Award Number: R01HL141353

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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