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Ca2+ and ROS Crosstalk Signaling in Cardiac Mitochondria

Award Number: R01HL093671
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2010
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Ca2+ and ROS Crosstalk Signaling in Cardiac Mitochondria - Maintaining mitochondrial function is critical for everyday operation of the heart. Proper mitochondrial function requires maintaining regulated and selective permeability of the mitochondrial inner membrane to ions and metabolites. Mitochondrial permeability transition occurs when the inner membrane loses its selective permeability by opening of a large-conductance nonselective channel, the permeability transition pore (PTP). High concentrations of mitochondrial Ca2+ and reactive oxygen species (ROS) are known to open PTP. PTP opening depolarizes mitochondria and causes mitochondrial swelling; thus, sustained opening of PTP leads to mitochondrial dysfunction and cell death, which is associated with many cardiovascular diseases including ischemia-reperfusion (I-R) injury and heart failure. Therefore, understanding how PTP is regulated has significant clinical value. It has long been known that increasing mitochondrial Ca2+ concentration opens PTP. More recently, mitochondrial dynamics mediated by fission and fusion have also been suggested to be involved in regulating PTP. However, the mechanisms by which Ca2+ and mitochondrial dynamics regulate PTP remain unknown. Our new findings show that increasing mitochondrial Ca2+ induces phosphorylation of cyclophilin D (CypD) through GSK-3β activation in mitochondria. Furthermore, we have found a transient opening of PTP (tPTP) that is distinct from conventional PTP and is regulated by mitochondrial dynamics proteins. Inhibition of the fission protein Drp1 increases this novel tPTP. Importantly, the inner membrane fusion protein OPA1 was found to be a critical factor for the novel tPTP. Although Drp1 inhibition is known to decrease pathologic PTP opening and reduce myocardial infarction in I-R, the mechanism of this fission inhibition-mediated protection is unknown. We postulate that the mitochondrial dynamics-mediated novel tPTP is a structurally distinct entity from conventional PTP, and thus in pathological conditions, can serve as a relief valve for excess matrix Ca2+ and proton gradient that induces ROS overproduction; as such, it could thereby prevent pathologic opening of PTP. Supported by our findings, the Central Hypothesis is that CypD phosphorylation induced by matrix Ca2+ is a key event for PTP opening, while mitochondrial dynamics regulates novel tPTP, and their interplay determines cardiac pathology outcomes. We will test this hypothesis by three specific aims: (1) to determine the mechanism of Ca2+-induced PTP opening, (2) to determine the mechanism of mitochondrial dynamics-regulated novel tPTP opening, and (3) to investigate the interplay between conventional PTP and novel tPTP in the pathological setting. The proposed studies will utilize advanced in vitro and in vivo cell and molecular biological approaches along with new fluorescence-based assays. Completion of the proposed studies will generate a new paradigm for the regulatory mechanisms of different forms of PTP and their functional interplay. The new findings will provide mechanistic basis for a new therapeutic strategy to decrease heart I-R injury and other cardiac pathology associated with PTP.


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 = $0 )
2025	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	12	11/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $506,880 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	12	2/11/2023	NON-COMPETING CONTINUATION	$50,688
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	12	11/16/2022	NON-COMPETING CONTINUATION	$456,192
														Subtotal = $506,880

Issue Date FY: 2022 ( Subtotal = $506,880 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	11	11/5/2021	NON-COMPETING CONTINUATION	$456,192
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	11	6/8/2022	NON-COMPETING CONTINUATION	$50,688
														Subtotal = $506,880

Issue Date FY: 2021 ( Subtotal = $506,880 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	10	12/1/2020	NON-COMPETING CONTINUATION	$456,192
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	10	5/24/2021	NON-COMPETING CONTINUATION	$50,688
														Subtotal = $506,880

Issue Date FY: 2020 ( Subtotal = $523,438 )
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	9	11/30/2019	COMPETING CONTINUATION	$523,438
2020	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	8	3/23/2020	NON-COMPETING CONTINUATION	$0
2020	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	8	11/29/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $523,438

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	8	4/16/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $387,500 )
2017	2017	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	8	4/17/2017	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2016 ( Subtotal = $387,500 )
2016	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	7	4/13/2016	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2015 ( Subtotal = $381,687 )
2015	2015	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	6	3/19/2015	NON-COMPETING CONTINUATION	$381,687
														Subtotal = $381,687

Issue Date FY: 2014 ( Subtotal = $387,500 )
2014	2014	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	5	7/11/2014	COMPETING CONTINUATION	$387,500
2014	2013	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	4	7/9/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,500

Issue Date FY: 2013 ( Subtotal = $365,211 )
2013	2013	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	4	8/1/2013	NON-COMPETING CONTINUATION	$19,948
2013	2013	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	4	1/18/2013	NON-COMPETING CONTINUATION	$345,263
														Subtotal = $365,211

Issue Date FY: 2012 ( Subtotal = $383,625 )
2012	2012	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	3	2/18/2012	NON-COMPETING CONTINUATION	$383,625
														Subtotal = $383,625

Issue Date FY: 2011 ( Subtotal = $387,187 )
2011	2011	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	2	5/25/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$387,187
2011	2010	UNIVERSITY OF ROCHESTER	910 GENESEE STREET SUITE 200	ROCHESTER	NY	14611	MONROE	USA	Cardiovascular Diseases Research	000	1	5/24/2011	NEW	$0
														Subtotal = $387,187

Issue Date FY: 2010 ( Subtotal = $379,083 )
2010	2010	UNIVERSITY OF ROCHESTER	910 GENESEE STREET SUITE 200	ROCHESTER	NY	14611	MONROE	USA	Cardiovascular Diseases Research	001	1	12/30/2009	NEW	$0
2010	2010	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	1	12/28/2009	NEW	$379,083
														Subtotal = $379,083

Grand Total All Awards = $5,103,371

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Ca2+ and ROS Crosstalk Signaling in Cardiac Mitochondria

Award Number: R01HL093671

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2010

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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