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Interaction of mitochondrial fusion and transmembrane potential in diabetic cardiovascular damage

Award Number: SC3GM116669
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Interaction of mitochondrial fusion and transmembrane potential in diabetic cardiovascular damage - PROJECT SUMMARY/ABSTRACT This proposal explores the interaction of mitochondrial fusion dynamics and transmembrane potential (∆ψm) as an underlying mechanism and translational target in diabetic cardiovascular damage. Type 2 diabetes mellitus is a rapidly-increasing public health concern, causing decreased cardiac efficiency which is the leading cause of mortality among Type 2 diabetics. A range of clinical and experimental data suggests that the cytokine-mediated inflammation that drives diabetic pathology directly damages mitochondria, the organellar network responsible for cellular bioenergetics. Crucially, however, it is unknown what level of mitochondrial damage can be sustained in highly-oxidative cardiac cells before pathology ensues. Our current SC3 support has provided novel mechanistic insights motivating the proposed aims: 1) to explore how the OMA1 stress-responsive protease is activated by loss of ∆ψm, 2) the role of OPA1 levels in determining mitochondrial fusion homeostasis, and 3) the time-dependent nature of ∆ψm-sensitive mitochondrial fusion dynamics. These experiments will leverage our published cell-based imaging and functional assays to further explore this gap in knowledge. To maintain bioenergetic homeostasis, mitochondria balance their organization between a united, reticular network (OPA1-mediated fusion) and a fragmented population of individual organelles (DRP1-mediated fission). The ∆ψm across the mitochondrial inner membrane is required for mitochondrial fusion, linking organellar function and structural dynamics: we demonstrated previously that a sharply-defined threshold of 34% ∆ψm is required for mitochondrial fusion. Strikingly, our current data indicates that a similar threshold exists in cardiac-derived cells, and that this threshold is mediated by OMA1, a stress- response protease that cleaves the mitochondrial OPA1 fusion protein in response to low ∆ψm. Further, our data suggests that novel intramolecular domains are required for OMA1 to sense loss of ∆ψm. Our project will mechanistically explore this threshold, as well as the impacts of cytokine-mediated damage on ∆ψm and fusion dynamics and the time-integrated nature of mitochondrial stress-sensitive dynamics. This research has strong potential to inform a novel translational approach to protect cardiac mitochondria against cytokine-mediated damage.


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: 2023 ( Subtotal = $108,975 )
2023	2023	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	002	8	6/13/2023	NON-COMPETING CONTINUATION	$108,975
2023	2020	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	001	5	4/7/2023	COMPETING CONTINUATION	-$48,589
2023	2019	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	4	4/7/2023	NON-COMPETING CONTINUATION	$48,589
														Subtotal = $108,975

Issue Date FY: 2022 ( Subtotal = $108,975 )
2022	2022	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	7	6/24/2022	NON-COMPETING CONTINUATION	$108,975
														Subtotal = $108,975

Issue Date FY: 2021 ( Subtotal = $108,975 )
2021	2021	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	6	6/22/2021	NON-COMPETING CONTINUATION	$108,975
2021	2020	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	002	5	7/30/2021	COMPETING CONTINUATION	$107,591
2021	2019	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	001	4	7/30/2021	NON-COMPETING CONTINUATION	-$107,591
														Subtotal = $108,975

Issue Date FY: 2020 ( Subtotal = $108,975 )
2020	2020	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	001	5	6/26/2020	COMPETING CONTINUATION	$108,975
2020	2019	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	4	6/25/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $108,975

Issue Date FY: 2019 ( Subtotal = $108,975 )
2019	2019	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	2102 TREASURE HILLS BLVD STE 3.100	HARLINGEN	TX	78550	CAMERON	USA	Biomedical Research and Research Training	000	4	2/20/2019	NON-COMPETING CONTINUATION	$108,975
														Subtotal = $108,975

Issue Date FY: 2018 ( Subtotal = $108,975 )
2018	2018	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	2102 TREASURE HILLS BLVD STE 3.100	HARLINGEN	TX	78550	CAMERON	USA	Biomedical Research and Research Training	001	3	5/11/2018	NON-COMPETING CONTINUATION	$10,898
2018	2018	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	2102 TREASURE HILLS BLVD STE 3.100	HARLINGEN	TX	78550	CAMERON	USA	Biomedical Research and Research Training	000	3	2/27/2018	NON-COMPETING CONTINUATION	$98,077
														Subtotal = $108,975

Issue Date FY: 2017 ( Subtotal = $108,975 )
2017	2017	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	2102 TREASURE HILLS BLVD STE 3.100	HARLINGEN	TX	78550	CAMERON	USA	Biomedical Research and Research Training	001	2	6/20/2017	NON-COMPETING CONTINUATION	$10,898
2017	2017	UNIVERSITY OF TEXAS RIO GRANDE VALLEY (UTRGV), THE	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	2	2/13/2017	NON-COMPETING CONTINUATION	$98,077
														Subtotal = $108,975

Issue Date FY: 2016 ( Subtotal = $108,975 )
2016	2016	UNIVERSITY OF TEXAS RIO GRANDE VALLEY (UTRGV)	1201 W. UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	1	3/1/2016	NEW	$108,975
														Subtotal = $108,975

Grand Total All Awards = $871,800

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Interaction of mitochondrial fusion and transmembrane potential in diabetic cardiovascular damage

Award Number: SC3GM116669

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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