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Regulation of mitochondrial calcium uniporter in the heart

Award Number: R01HL136757
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Regulation of mitochondrial calcium uniporter in the heart - PROJECT SUMMARY Recent discovery of the molecular identity of pore-forming subunit of the mitochondrial Ca2+ uniporter (encoded by MCU gene) provides new possibilities for applying genetic approaches to study the mitochondrial Ca2+ (mtCa2+) influx mechanism. T hough the alteration of MCU function and mtCa2+ overload are frequently observed in non- cardiac human diseases, cardiomyocytes (ACMs) and MCU function contribute to the pathology . Recently, I reported that a post-translational modification (PTM) of MCU (tyrosine it is still not clear how mtCa2+ in adult phosphorylation) is one of the critical regulatory mechanisms for upregulating MCU function in ACMs. PTM of MCU initiates overload, -dependent ROS overproduction and activation of apoptotic signaling under alpha1-adrenoceptor (alpha1-AR) stimulation, suggesting that PTM of MCU plays an important role in the development of cardiac dysfunction under Gq-protein-coupled receptor (GqPCR) stimulation, which is one of the major causes of heart failure (HF) in vivo. In addition to the discovery of the PTM of MCU, I identified a form of transcriptional/post-transcriptional regulation of MCU, namely the existence of alternative transcript variants (“short- form” MCU, termed MCU-S) in human and mouse in addition to the original MCU (“long form” MCU, renamed MCU-L). Importantly, MCU-S is highly expressed in non-excitable cells including adult cardiac fibroblast (ACFs). Our preliminary data show that introduction of MCU-S enhances the formation of Ca2+-permeable channels at the plasma membrane (PM). In addition, the PM-localized MCU channel (PM-MCU) formed by MCU-S activates glycolysis followed by acceleration of ATP production in the cytoplasm, possibly due to the increase in local [Ca2+]c beneath the PM. These preliminary findings indicate an important role of PM-MCU channels for energy metabolism especially in non-excitable cells (such as ACFs). We also determined that the manipulation of MCU-S/MCU-L ratio mtCa2+ mtCa2+ can secondarily modulate the driving force of MCU-channel trafficking to IMM, which eventually inhibits the mtCa2+ uptake, mtCa2+ -dependent ROS overproduction and activation of apoptotic signaling under alpha1-AR stimulation. Therefore, I hypothesize that the MCU gene encodes two isoforms that form both mitochondrial and non- mitochondrial MCU channels; novel transcript variant MCU-S forms a PM-MCU channels that regulate cell’s metabolism and inhibits the MCU-channel trafficking to IMM. To test the hypothesis, I will investigate whether MCU-S forms Ca2+-permeable MCU channels at PM and is involved in the mechanism for the activation of glycolysis to accelerate ATP production in the cytoplasm in primary ACMs and ACFs (Aim.1). I will next test whether switching the main variant from MCU-L to MCU-S protects the heart from mtCa2+-overload-mediated apoptotic death, energy depletion and cardiac dysfunction under GqPCR stimulation in vivo (Aim.2). The outcome of this project is expected to lead to a novel treatment strategy for cases of HF under GqPCR stimulation that involve mtCa2+ overload, oxidative stress, energy depletion and ACM death. Moreover, elucidation of the role of MCU variants will provide us novel insights into the molecular basis of mtCa2+ handling in the heart.


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 = -$1 )
2024	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	5	1/18/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	5	5/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $385,000 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	5	5/12/2021	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2020 ( Subtotal = $385,000 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	4	4/15/2020	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2019 ( Subtotal = $466,754 )
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	004	3	5/21/2019	NON-COMPETING CONTINUATION	$385,000
2019	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	000	2	11/16/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	003	2	2/12/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,511
2019	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	001	2	2/5/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$81,754
2019	2017	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	002	1	2/12/2019	NEW	-$1,511
														Subtotal = $466,754

Issue Date FY: 2018 ( Subtotal = $299,466 )
2018	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cardiovascular Diseases Research	001	2	8/24/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$381,220
2018	2017	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	002	1	8/29/2018	NEW	-$81,754
2018	2017	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	1	8/23/2018	NEW	$0
														Subtotal = $299,466

Issue Date FY: 2017 ( Subtotal = $398,230 )
2017	2017	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	1	6/7/2017	NEW	$398,230
														Subtotal = $398,230

Grand Total All Awards = $1,934,449

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Regulation of mitochondrial calcium uniporter in the heart

Award Number: R01HL136757

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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