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Investigating Calcium Homeostasis During a Key Mitochondrial Stress Pathway

Award Number: F31AG072716
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/16/2022
PERIOD OF PERFORMANCE END DATE: 03/15/2023

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Investigating Calcium Homeostasis During a Key Mitochondrial Stress Pathway - PROJECT SUMMARY Mitochondria are central to cellular metabolism, signaling, protein homeostasis, immunity, and apoptosis. One of the ways by which mitochondria respond effectively to changing mitochondrial and cellular needs is with calcium signaling. Ca2+ ions enter the mitochondrial matrix through a protein channel called the mitochondrial calcium uniporter (MCU) that resides on the inner membrane of the mitochondria. Altered MCU-mediated mitochondrial calcium signaling is involved in a variety of human neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and hereditary spastic paraplegia. Furthermore, these same diseases have been shown to exhibit the hallmarks of mitochondrial protein stress, including elevated protein levels of mitochondrial chaperones. Mitochondrial protein stress can be caused by misfolded or unfolded proteins accumulating within the mitochondria. Preliminary studies in the Sancak Lab suggest that MCU-mediated calcium signaling plays a critical role in facilitating the mitochondrial protein stress response. Data showing increased MCU mRNA and protein during mitochondrial protein stress suggests that MCU is upregulated as part of a mitochondrial protein stress response. Even more intriguingly, relative to WT and MCU rescue cell lines, MCU knockout cells have lower baseline levels of mitochondrial chaperones and ATF4, a transcription factor central to cellular stress responses. Furthermore, when mitochondrial protein stress is induced, the mRNA levels of ATF4 and these chaperones increase much less than in WT or rescue cells. The central hypothesis of this proposal is that altered MCU regulation and calcium signaling comprise a heretofore uncharacterized pathway that regulates transcription in response to mitochondrial protein stress. Aim 1 will offer new insight about the molecular mechanisms regulating the transcription, translation and protein stability of MCU. The functional studies of Aim 2 will reveal how mitochondrial protein stress alters calcium signaling and transcription. Successful completion of this proposal will advance the field by identifying novel players in the poorly understood mitochondria-to-nuclear signaling pathway. These findings will also uncover a new function for mitochondrial calcium signaling in the regulation of a transcriptional response central to the mitochondrial protein stress response, and will reveal potential therapeutic targets for the treatment of neurodegenerative disease. Completion of Aim 1 will provide valuable training in pairing gene editing with pharmacological tools to dissect the function and regulation of MCU, a protein with great disease relevance. Completion of Aim 2 will provide training in using laser-scanning confocal microscopy and live imaging techniques to study mitochondrial stress. The University of Washington is very well funded and well equipped. Its top tier faculty, staff, and technicians, and variety of state-of-the-art facilities will ensure the success of this proposed work.


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 = -$33,959 )
2025	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	000	2	12/19/2024	NON-COMPETING CONTINUATION	-$22,752
2025	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	001	2	1/23/2025	NON-COMPETING CONTINUATION	-$11,207
														Subtotal = -$33,959

Issue Date FY: 2023 ( Subtotal = $45,114 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	001	2	2/23/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	000	2	11/18/2022	NON-COMPETING CONTINUATION	$44,172
														Subtotal = $45,114

Issue Date FY: 2022 ( Subtotal = $43,781 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	002	1	5/3/2022	NEW	$717
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	001	1	1/12/2022	NEW	$0
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	000	1	1/12/2022	NEW	$43,065
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Aging Research	003	1	8/30/2022	NEW	-$1
														Subtotal = $43,781

Grand Total All Awards = $54,936

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Investigating Calcium Homeostasis During a Key Mitochondrial Stress Pathway

Award Number: F31AG072716

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/16/2022

PERIOD OF PERFORMANCE END DATE: 03/15/2023

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