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Molecular link between MCU and Mrs2p channels for mitochondrial ion homeostasis and energy metabolism

Award Number: R00HL138268
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Molecular link between MCU and Mrs2p channels for mitochondrial ion homeostasis and energy metabolism - Summary In cardiomyocytes the high metabolic demand of contractility emphasizes the need for an efficient and tightly controlled energy producing system. Oxidative Phosphorylation (OxPhos) serves the need of myocardium and as such the site of OxPhos is the mitochondria that represents a central control dogma to ensure that energy demands are met. In mitochondria, Ca2+ is proposed to be the link between EC coupling (ECC) and OxPhos and has been shown to modulate mitochondrial metabolism through the activation of Ca2+-dependent dehydrogenases. It is a long standing mystery on how mitochondrial calcium ([Ca ]m) uptake is tightly regulated during physiology and 2+ pathology. The [Ca ]m uptake is facilitated by the large electrochemical gradient across the inner mitochondrial 2+ membrane and mediated by the Mitochondrial Calcium Uniporter (MCU). MCU is a hetero-oligomeric complex and known to be regulated by several of its interacting partners MICUs, MCUR1, EMRE and MCUb. But there is a lack of knowledge on the exact molecular mechanism of MCU regulation. Our recent structural insight of the MCU channel revealed an acidic patch where cations can bind and regulate MCU activity. Consistent with this, other Ca2+ channels including L-type, ryanodine receptors (RyRs), Inositol 1,4,5 triphosphate receptors (IP3Rs), and Ca release activated 2+ Ca2+ channels are known to be regulated by a negative feedback mechanism. Our discovery of this long-sought regulatory mechanism, uniquely positions us to study the divalent cation based regulation of MCU during pathophysiological condition. Thus I hypothesize that under physiological conditions mitochondrial matrix Mg2+- binding-induced inactivation of MCU may be a protective buffering mechanism for [Ca ]m overload mediated cell 2+ death that is pertinent to cardiomyocyte energy metabolism. Mg2+ being the most abundant divalent cation is known to play important roles in regulating Ca2+ and K+ channels of plasma membrane. In mitochondria, matrix Mg2+ homeostasis is maintained by a selective CorA transport family protein, Mrs2p. Thus, the current proposal aims to delineate the mechanism by which mitochondrial matrix magnesium ([Mg ]m) contributes to the regulation of MCU 2+ activity, mitochondrial Ca2+ homeostasis and bioenergetics. To uncover the molecular link between and MCU and Mrs2p channels, I will generate knockout, and functional domain (loss/gain of function) knock-in mutant model systems using CRISPR/Cas9 mediated gene targeting to study the regulation of MCU-mediated [Ca ]m 2+ uptake by matrix Mg2+. We hypothesize that mitochondrial matrix will be overloaded with Ca2+ in cells that lack Mrs2p and its functional domain (GMN). Conversely, we also hypothesize that the knock-in mutant corresponding to the acidic patch of Mrs2p will serve as a gain-of- function mutant and will alleviate MCU- mediated Ca2+ overload during pathological conditions including I/R injury and protect cardiomyocytes from necrotic cell death. The proposed study will reveal how MCU regulation by divalent cations provide a therapeutic strategy for I/R injury.


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 = -$88,010 )
2024	2021	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	5	1/18/2024	NON-COMPETING CONTINUATION	-$88,010
														Subtotal = -$88,010

Issue Date FY: 2023 ( Subtotal = $37,642 )
2023	2019	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	3	10/17/2022	EXTENSION WITH OR WITHOUT FUNDS	$37,642
														Subtotal = $37,642

Issue Date FY: 2021 ( Subtotal = $249,000 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	5	5/25/2021	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2020 ( Subtotal = $249,000 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	4	5/26/2020	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2019 ( Subtotal = $249,000 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	3	6/6/2019	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $696,632

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Molecular link between MCU and Mrs2p channels for mitochondrial ion homeostasis and energy metabolism

Award Number: R00HL138268

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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