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Molecular Physiology of Mitochondrial Calcium Uniporter

Award Number: R01GM145806
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: 06/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Molecular Physiology of Mitochondrial Calcium Uniporter - Project Summary The mitochondrial calcium uniporter complex (MCUcx) is a highly-selective, tetrameric Ca2+ channel that plays a primary role in transporting Ca2+ from the cytoplasm into the mitochondrial matrix. Although Ca2+ uptake by mitochondria plays a crucial role in stimulating ATP production, matrix Ca2+ overload can trigger opening of the mitochondrial permeability transition pore, leading to cell death. MCU dysfunction has been implicated in several pathological conditions such as heart failure, ischemia–reperfusion injury, neurodegeneration, cancer and skeletal muscle dystrophies. Recent biochemical and structural studies have shown that the MCUcx is a macromolecular complex composed of a pore-forming MCU subunit, an essential subunit EMRE, and EF-hand domain-containing MICU1–3 subunits. How each subunit of the MCU complex comes together and regulates mitochondrial Ca2+ entry has been the focus of many recent studies. Using direct mitochondrial patch-clamp methodology and an innovative heterologous expression system, we recently performed a comprehensive structure–function analysis of the MCUcx in the inner mitochondrial membrane. This expression system consists of gene knockout of each individual subunit of the MCUcx (more than 6 different knockout lines were generated by CRISPR/cas9) and is readily amenable to different patch-clamp configurations with a high success rate. Using this system and the patch-clamp technique, we propose to answer central questions in the field: 1) Where is the MCU gate, and how is this gate regulated by Ca2+ and MCU accessory subunits? and 2) How do the unique features in the MCU macromolecular structures (as revealed by recent structural studies) relate to MCU gating and function? Accomplishment of the aims of this proposal will provide better understanding of the mechanisms that regulate Ca2+ entry via the MCU and create an essential framework for the development of pharmacological interventions that target MCU gating for therapeutic purposes.


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: 2026 ( Subtotal = $339,900 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	4	4/9/2026	NON-COMPETING CONTINUATION	$339,900
														Subtotal = $339,900

Issue Date FY: 2025 ( Subtotal = $339,900 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	6/10/2025	NON-COMPETING CONTINUATION	$339,900
														Subtotal = $339,900

Issue Date FY: 2024 ( Subtotal = $339,900 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	4/19/2024	NON-COMPETING CONTINUATION	$305,910
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	2	6/10/2024	NON-COMPETING CONTINUATION	$33,990
														Subtotal = $339,900

Issue Date FY: 2023 ( Subtotal = $339,900 )
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	1	6/9/2023	NEW	$339,900
														Subtotal = $339,900

Grand Total All Awards = $1,359,600

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Molecular Physiology of Mitochondrial Calcium Uniporter

Award Number: R01GM145806

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: 06/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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